Indene derivatives as pharmaceutical agents

ABSTRACT

Compounds of formula (Ia): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 5  and R 6  are defined herein, as well as other indene derivatives are disclosed herein. Pharmaceutical compositions containing the compounds and methods of using the compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 60/463,216, filed Apr. 15, 2003, where this provisionalapplication is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to indene derivatives, methods of using thederivatives and pharmaceutical compositions containing same.

2. Description of the Related Art

The normal inflammatory response is an essential localized host responseto invading microorganisms or tissue injury which involves cells of theimmune system. The inflammatory response allows the body to specificallyrecognize and eliminate an invading organism and/or repair tissueinjury. The classic signs of inflammation include redness (erythema),swelling (edema), pain and increased heat production (pyrema) at thesite of injury. Many of the acute changes at the site of inflammationare either directly or indirectly attributable to the massive influx ofleukocytes (e.g., neutrophils, eosinophils, lymphocytes, monocytes)which is intrinsic to this response. Leukocytic infiltration andaccumulation in tissue results in their activation and subsequentrelease of inflammatory mediators such as LTB₄, prostaglandins, TNF-α,IL-1β, IL-8, IL-5, IL-6, histamine, proteases and reactive oxygenspecies for example.

Normal inflammation is a highly regulated process that is tightlycontrolled at several levels for each of the cell types involved in theresponse. For example, expression of the pro-inflammatory cytokine TNF-αis controlled at the level of gene expression, translation,post-translational modification, and release of the mature form from thecell membrane. Pro-inflammatory responses are normally countered byendogenous anti-inflammatory mechanisms such as generation of IL-10 orIL-4. A characteristic of a normal inflammatory response is that it istemporary in nature and is followed by a resolution phase which bringsthe state of the tissue back to its prior condition. The resolutionphase is thought to involve up-regulation of anti-inflammatorymechanisms, such as IL-10, as well as down-regulation of thepro-inflammatory processes.

Inflammatory disease occurs when an inflammatory response is initiatedthat is inappropriate and/or does not resolve in the normal manner, butrather persists and results in a chronic inflammatory state. Disease mayalso involve a perturbation of the cellular immune response that resultsin recognition of host proteins (antigens) as foreign. Here, theinflammatory response becomes misdirected at host tissues with effectorcells targeting specific organs or tissues often resulting inirreversible damage. The self-recognition aspect of auto-immune diseaseis often reflected by the clonal expansion of T-cell subsetscharacterized by a particular T-cell receptor (TCR) subtype in thedisease state. Often inflammatory disease is also characterized by animbalance in the levels of T-helper (Th) subsets (i.e., Th1 cells vs.Th2 cells). Inflammatory disease may be systemic (e.g. lupus) orlocalized to particular tissues or organs (e.g. asthma), and exerts anenormous personal and economic burden on society. Examples of some ofthe most common and problematic inflammatory diseases are asthma,multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease,psoriasis, and atopic dermatitis.

Therapeutic strategies aimed at curing inflammatory diseases usuallyfall into one of two categories: (a) down-modulation of processes thatare up-regulated in the disease state or (b) up-regulation ofanti-inflammatory pathways in the affected cells or tissues. Mostregimes currently employed in the clinic fall into the first category.Some examples of which are corticosteroids and non-steroidalanti-inflammatory drugs (NSAIDs).

Many of the tissue, cellular and biochemical processes which areperturbed in inflammatory disease have been elucidated and this hasallowed the development of experimental models or assays to mimic thedisease state. These assays and models enable screening and selection ofcompounds with a reasonable probability of therapeutic efficacy in therelevant inflammatory disease. Despite the use of these models,effective drugs have not been discovered for many inflammatory diseases.There is a significant need for therapeutic agents that effectivelyarrest or reverse disease progression for disease states or pathologiessuch as asthma, chronic obstructive pulmonary disease, multiplesclerosis, psoriasis, and inflammatory bowel disease.

BRIEF SUMMARY OF THE INVENTION

The compounds of the present invention are useful as anti-inflammatoryagents.

Accordingly, in one aspect the invention provides compounds of formula(I):

wherein:

the A, C or D ring is independently fully saturated, partially saturatedor fully unsaturated;

C1, C4, C11, C12, C15 and C16 are each independently substituted withtwo of the following, which are independently selected: hydrogen, alkyl,—R⁸—OR⁷, or —R⁸—N(R⁷)₂, provided that C4 is not substituted by twomethyl groups;

C9 and C14 are each independently substituted with hydrogen, alkyl,—R⁸—OR⁷, or —R⁸—N(R⁷)₂;

R¹ is —OR⁷ or —N(R⁷)₂;

R² and R³ are each independently selected from the group consisting of—R⁸—OR⁷, —R⁸—OC(O)R⁹, —R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹,—R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain;

as a single stereoisomer, a mixture of stereoisomers, or as a racemicmixture of stereoisomers;

or a pharmaceutically acceptable salt, solvate or prodrug thereof, inisolation or in a mixture.

In another aspect, the invention provides compounds of formula (II):

wherein:

the A, C or D ring is independently fully saturated, partially saturatedor fully unsaturated;

C1, C2, C4, C11, C12, C15 and C16 are each independently substitutedwith:

(a) one of the following: ═O, ═C(R¹⁴)₂, ═C═C(R¹⁴)₂, —[C(R¹⁴)₂]_(n)—(where n is 2 to 6) and —O—[C(R¹⁴)₂]_(m)—O— (where m is 1 to 6); or

(b) two of the following, which are independently selected: —R¹⁴, —OR¹⁵and —N(R¹⁶)₂;

C3 is substituted with two of the following, independently selected:—R¹⁴, —OR¹⁵ and —N(R¹⁶)₂;

C5, C8, C9, C10, C13, C14 and C17 are each independently optionallysubstituted with one of the following: —R¹⁴, —OR¹⁵ and —N(R¹⁶)₂;

R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen, halo, ═O, —OR¹⁵, —N(R¹⁶)₂ and a C₁₋₃₀ organic moiety;

R¹³ is —R¹⁴, —OR¹⁵, —N(R¹⁶)₂, ═C(R¹⁴)₂, ═C═C(R¹⁴)₂, —[C(R¹⁴)₂]_(n)—(where n is 2 to 5) or —O—[C(R¹⁴)₂]_(m)—O— (where m is 1 to 5);

each R¹⁴ is independently selected from hydrogen, halo and C₁₋₃₀ organicmoiety where two geminal R¹⁴ groups may together form a ring with thecarbon to which they are attached;

each R¹⁵ is independently selected from the group consisting ofhydrogen, an oxygen protecting group such that —OR¹⁵ is a protectedhydroxy group, a leaving group initiator such that —OR¹⁵ is a leavinggroup and a C₁₋₃₀ organic moiety that may optionally contain at leastone heteroatom selected from the group consisting of boron, halogen,nitrogen, oxygen, phosphorus, silicon and sulfur, where vicinal —OR¹⁵groups together with the carbons to which they are attached may form acyclic structure that protects vicinal hydroxy groups and where geminal—OR¹⁵ groups together with the carbon to which they are attached, mayform a cyclic structure that protects a carbonyl group;

each R¹⁶ is independently selected from the group consisting ofhydrogen, —OR¹⁷, oxygen (so as to form a nitro or an oxime group), and aC₁₋₃₀ organic moiety that may optionally contain at least one heteroatomselected from the group consisting of boron, halogen, nitrogen, oxygen,phosphorus, silicon and sulfur; or two R¹⁶ groups, together with thenitrogen to which they are attached, form a heterocyclic ring; and

each R¹⁷ is independently selected from hydrogen and a C₁₋₃₀hydrocarbyl; as a single stereoisomer, a mixture of stereoisomers, or asa racemic mixture of stereoisomers;

or a pharmaceutically acceptable salt, solvate or prodrug thereof, inisolation or in a mixture;

provided, however, that

(1). C4 can not be substituted with two methyl groups

(2) R¹³ can not be ═0 or 6-methylhept-2-yl;

(3) when C17 is substituted with hydrogen, R¹³ can not be —OH or —OC(O)Rwhere R is methyl, ethyl, phenyl or cyclohexyl;

(4) when C1, C2, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C8, C9, C14 andC17 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)H, R¹³ can not be—C(CH₃)HCH₂CH₂C(O)OCH₃ or —C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H;

(5) when C1, C2, C4, C11, C12, and C15 are each substituted with twohydrogens, C16 is substituted with hydrogen and hydroxy, C8, C9, C14 andC17 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, C3 is substituted with hydrogen and hydroxy, R¹¹ is ═O, andR¹² is —CH₂C(O)OH or —CH₂C(O)OCH₃, R¹³ can not be—C(CH₃)HNHCH₂CH₂N(CH₃)₂, —C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H, or —C(CH₃)H—R(where R is 5-methylpiperidin-2-yl);

(6) when C1, C2, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C4 issubstituted with two hydrogens or C4 is double bonded to C3, C8, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is ═O, and R¹² is —CH₂CN, R¹³ can not be—C(O)OCH₃;

(7) when C1, C2, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C9, C14 and C17are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is ═O, and R¹² is ═CHC(O)H, R¹³ can not be—C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H;

(8) when C1, C2, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C8, C9, C14 andC17 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is ═O, and R¹² is —CH₂CH₃, R¹³ can not be—C(CH₃)HOC(O)CH₃;

(9) when C1, C2, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C5, C9, C14 andC17 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is hydroxy, and R¹² is ═CHCH₂OH, R¹³ can not be—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H, or —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H,—C(CH₃)HCH₂CH₂C(CH₂)C(CH₃)₂H, or —C(CH₃)HCHC[CH₂C(CH₃)₂H]H;

(10) when C1, C2, C4, C11, C12, and C15 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C5, C8, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, C16 is substituted with two hydrogens or withone hydrogen and hydroxy, R¹¹ is hydroxy, and R¹² is —CH₂CH₂OH, R¹³ cannot be —C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H, —C(CH₃)HCH₂OH, —CH₂OH, or—C(CH₃)H—R (where R is 5-methylpiperidin-2-yl);

(11) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and hydroxy, C5, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is hydroxy, and R¹² is —CH₂CH₃, R¹³ can notbe —C(CH₃)HCH₂C(CH₃)HC(CH₃)₂H or —C(OH)HCH₃;

(12) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and hydroxy, C5, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is hydroxy, and R¹² is —CHCH₂, R¹³ can notbe —C(OH)HCH₃;

(13) when C1, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C2 is substituted with hydrogen and hydroxy, C3 issubstituted with hydrogen and hydroxy, C5, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is —C(O)OH, and R¹³ is —C(CH₃)HC(OH)HC(OH)HC(CH₂CH₃)HC(CH₃)₂H, R¹²can not be —CH₂SH or —CH₂SSCH₂R (where R is hydrogen or a C₁₋₃₀ organicmoiety);

(14) when C1, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C2 is substituted with two hydrogens or with hydrogen andhydroxy, C3 is substituted with hydrogen and hydroxy, C5, C8, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is —C(O)OH or —CH₂OH, and R¹² is —CH₂OH,R¹³ can not be —CH₂OH, —C(CH₃)HC(OH)HC(OH)HC(CH₃)HC(CH₃)₂H or—C(CH₃)HC(OH)HC(OH)HC(CH₂CH₃)HC(CH₃)₂H;

(15) when C1, C2, C11, C12 and C15 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C4 issubstituted with hydrogen and methyl or with two hydrogens, C5 and C9are each substituted with hydrogen, C8 and C14 are each substituted withhydrogen or each are substituted with methyl, C10 and C13 are eachsubstituted with methyl, C16 is substituted with hydrogen and —OC(O)CH₃,R¹¹ is —C(O)H, and R¹² is —C(O)H, R¹³ can not be═C[C(O)OH]CH₂CH₂CHC(CH₃)₂ or —C(CH₃)HCH₂CH₂C(O)OCH₃;

(16) when C1, C2, C4, C11, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and hydroxy, C5, C8, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, C12 is substituted with hydrogen and hydroxy,R¹¹ is —CH₂C(O)OH or —CH₂C(O)OCH₃, and R¹² is —NH₂ or —N(CH₃)₃, R¹³ cannot be —C(CH₃)HCH₂CH₂C(O)OCH₃ or —C(CH₃)HCH₂CH₂C(O)OH;

(17) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and hydroxy, C5, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is —NH₂ or —N(CH₃)₂, and R¹² is —CH₂C(O)OHor —CH₂C(O)OCH₃, R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OCH₃ or—C(CH₃)HCH₂CH₂C(O)OH;

(18) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and hydroxy, C8, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is ═NNHC(NH)NH₂, and R¹² is —CH₂CH₂C(O)OH,R¹³ can not be —C(CH₃)NNHC(NH)NH₂);

(19a) when C1, C2, C4, C11 and C12 are each substituted with twohydrogens, C3 is substituted with ═O, C8, C14 and C17 are eachsubstituted with hydrogen, C9 is substituted with hydrogen or hydroxy,C10 and C13 are each substituted with methyl, C15 is substituted withtwo hydrogens or C15 is substituted with hydrogen and double bonded toC16, C16 is substituted with hydrogen or hydroxy and is double bonded toC15 or C16 is substituted with ═CH₂OH, R¹¹ is ═O, and R¹² is ═CHC(O)OH,R¹³ can not be —C(CH₃)HC(O)CH₂C(CH₃)HC(CH₃)₂H;

(19b) when C1, C2, C4, C11 and C12 are each substituted with twohydrogens, C3 is substituted with ═O, C8 and C14 are double bonded toeach other, C9 is substituted with hydroxy, C10 and C13 are eachsubstituted with methyl, C15 is substituted with hydrogen and doublebonded to C16, C16 is substituted with methoxy and double bonded to C15,C17 is substituted with hydrogen, R¹¹ is ═O, and R¹² is —CH₂C(O)OCH₃,R¹³ can not be —C(CH₃)HC(O)CH₂C(CH₃)HC(CH₃)₂H;

(20) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with ═O, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is ═O, and R¹² is —CH₂CN, R¹³ can not be —C(O)NHR (where R is5-trifluoromethyl-2-t-butylphenyl) or —C(O)OCH₃;

(21) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with ═O, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 is substituted with methyl or —CH₂OC(O)H,C13 is substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂CH₃ or —CH₂I,R¹³ can not be —C(O)CH₃;

(22) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with ═O, C5, C8, C9, C14 and C17 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, R¹¹ is —C(O)OH, and R¹² is —C(O)OH, R¹³ can not be—C(CH₃)HCH₂CH₂C(O)OH or —C(CH₃)HCH₂CH₂CH₃;

(23) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with ═O, C5, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is —CN, and R¹² is ═O, R¹³ can not be —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H;

(24) when C1, C2, C4, C12 and C15 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9, andC14 are each substituted with hydrogen, C11 is substituted with twohydrogens, hydrogen and hydroxy, or hydrogen and —OC(O)CH₃, C16 issubstituted with two hydrogens or ═CH₂, C17 is substituted withhydrogen, hydroxy or —OC(O)CH₃, C10 and C13 are each substituted withmethyl, R¹¹ is ═O, and R¹² is —CH₂C(O)OH, R¹³ can not be —CH₃, —CH₂CH₃,—C(O)CH₃, cyclopentanone, —C(CH₃)HOC(O)R (where R is phenyl),—C(CH₃)HCH₂CH₂C(O)OCH₃, —C(O)CH₂OC(O)CH₃ or—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H;

(25) when C1, C2, C4, C11, C12 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8 and C9 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, C14 is substituted with methyl or —OC(O)CH₃, C15 is substitutedwith two hydrogens or ═O, C17 is substituted with hydrogen or —OC(O)CH₃,R¹¹ is ═O, and R¹² is —CH₂C(O)H, R¹³ can not be —C(O)OCH₃, —C(O)CH₃ or—CH₃;

(26) when C1, C2, C4, C11, C12, and C15 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9, andC14 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, C16 is substituted with two hydrogens or forms a doublebond with C17, R¹¹ is ═O, and R¹² is —CH₂CN, R¹³ can not be —C(O)CH₃;

(27) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9,C14 and C17 are each substituted with hydrogen, C10 is substituted withhydrogen or —CH₂C(O)OH, C13 is substituted with methyl, R¹¹ is ═O, andR¹² is —CH₂I or —CH₂C(O)OCH₃, R¹³ can not be —C(O)CH₃;

(28) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9,C14 and C17 are each substituted with hydrogen, C10 is substituted withhydrogen or —CH₂C(O)OH, C13 is substituted with methyl, R¹¹ is ═O, andR¹² is —CH₂I, —CHCH₂, —CCH, —C(O)OCH₃ or —CH₂OCH₃, R¹³ can not be—C(CH₃)HOC(O)CH₃

(29) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is ═O, and R¹² is —CH₂NCO, —CH₂C(O)N₃ or—C(O)OH, R¹³ can not be —C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H;

(30) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9,and C14 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, C17 is substituted with —OC(O)CH₃, R¹¹ is ═O,and R¹² is —CH₂CHNNHR (where R is 2,4-dinitrophenyl), R¹³ can not be—CH₃;

(31) when C1, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C2 is substituted with hydrogen and —OC(O)CH₃, C3 issubstituted with hydrogen and —OC(O)CH₃, C5, C8, C9, C14 and C17 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, R¹¹ is —C(O)OH, and R¹² is —C(O)H, R¹³ can not be—C(CH₃)HCH₂CH₂CH₂CH₃;

(32) when C1, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C2 is substituted with hydrogen and —OC(O)CH₃, C3 issubstituted with hydrogen and —OC(O)CH₃, C5, C8, C9, C14 and C17 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, R¹¹ is —C(O)OH or —C(O)OCH₃, and R¹² is —C(O)H, —CH₂SSCH₂R(where R is hydrogen or a C₁₋₃₀ organic moiety), —CH₂OS(O)₂CH₃, or—CH₂OH, R¹³ can not be—C(CH₃)HC[OC(O)CH₃]HC[OC(O)CH₃]HC(CH₂CH₃)HC(CH₃)₂H;

(33) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C5, C8,C9, C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is —C(O)OH, and R¹² is —C(O)OH, R¹³ can notbe —C(CH₃)HCH₂CH₂C(O)OH;

(34) when C1, C2, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C4 issubstituted with hydrogen and methyl, C5, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is —CH₂C(O)H, and R¹² is ═O, R¹³ can not be—C(CH₃)HCH₂CH₂C(O)C(CH₃)₂H;

(35) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C5, C8,C9, C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, and R¹¹ and R¹² are both —CHNOCH₃ or—CHNOCH₂CH₃, R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OCH₃;

(36) when C1, C2, C4, C11, C12 and C15 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C5, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, C16 is substituted with hydrogen and —OC(O)CH₃,R¹¹ is —OC(O)CH₃, and R¹² is —CH₂CH₂OC(O)CH₃, R¹³ can not be —C(CH₃)HR(where R is 5-methyl-1-acetylpiperidin-2-yl);

(37) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and triisopropylsilyloxy,C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13 areeach substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)OH,—CH₂C(O)H, —CH₂CH₂N3, —CH₂CH₂OH, —CH₂CH₂OS(O)₂CH₃ or —CH₂C(O)N₃, R¹³ cannot be —C(O)N(CH₂CH₃)₂;

(38) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and triisopropylsilyloxy,C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13 areeach substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)OH,—CH₂C(O)H or —CH₂C(O)Cl, R¹³ can not be —C(O)OCH₃;

(39) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and triisopropylsilyloxy,C5, C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13are each substituted with methyl, and R¹¹ and R¹² are both —CHNOCH₃, R¹³can not be —C(CH₃)HCH₂CH₂C(O)OCH₃;

(40) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted hydrogen and —OC(O)R (where R is4-nitrophenyl or 3,5-dinitrophenyl), C5, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is —OH, and R¹² is —CH₂CH₂OC(O)R (where R is 4-nitrophenyl or3,5-dinitrophenyl), R¹³ can not be —C(CH₃)HCH₂OC(O)R (where R is4-nitrophenyl or 3,5-dinitrophenyl) or —C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H;

(41) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OCH₂OCH₃, C5, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is —CN, and R¹² is —OH or ═O, R¹³ can notbe —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H;

(42) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OCH₂CH₂CH₃, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)OH, R¹³ can notbe —OCH₂CH₂CH₃;

(43) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with ═NNHR (where is R is2,4-dinitrophenyl), C5, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, and R¹¹ and R¹²are both —C(O)OH, R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OH;

(44) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OCH₂R (where R isphenyl), C5, C9, C14 and C17 are each substituted with hydrogen, C10 andC13 are each substituted with methyl, R¹¹ is —CH₂C(O)H, and R¹² is ═O,R¹³ can not be —C(CH₃)HCH₂CH₂C(CH₃)HC(CH₃)₂H;

(45) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —CH₃, C8, C9, C14 andC17 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is ═O, and R¹² is —C(O)OH, R¹³ can not be —OC(CH₃)₃;and

(46) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(CH₃)₃, C5, C8,C9, C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is hydroxy, and R¹² is —CH₂OH, R¹³ can notbe —OC(CH₃)₃.

In another aspect, the invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and a compound offormula (I) or a compound of formula (II), as described above.

In another aspect, the invention provides a method of treating aninflammatory condition or disease in a mammal, which method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula (I) or a compound of formula (II), asdescribed above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical compositions and methodsuseful in the treatment and/or prevention of various disease conditions.For example, in one aspect, the present invention provides a method oftreating inflammation in a mammal, preferably a human. The methodincludes administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof, or an effective amount of a pharmaceuticalcomposition containing a compound of the invention or a pharmaceuticallyacceptable salt thereof.

Before describing the invention in further detail, certain definitionsas used herein are provided with the following definitions, and certainconventions used herein are also set forth.

DEFINITION OF TERMS

As used herein the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. For example, “acompound” refers to one or more of such compounds, while “the enzyme”includes a particular enzyme as well as other family members andequivalents thereof as known to those skilled in the art. As used in thespecification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to seven carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to seven carbon atoms, and whichis attached to the rest of the molecule by a single bond, e.g., ethenyl,prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to seven carbon atoms, and whichis attached to the rest of the molecule by a single bond, e.g., ethynyl,prop-2-ynyl, but-2-ynyl, pent-2-ynyl, penta-1,4-diynyl, and the like.

“Aryl” refers to refers to aromatic monocyclic or multicyclichydrocarbon ring system consisting only of hydrogen and carbon andcontaining from 6 to 19 carbon atoms, where the ring system may bepartially or fully saturated. Aryl groups include, but are not limitedto groups such as fluorenyl, phenyl and naphthyl. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, —R⁸—OR⁷, —R⁸—N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—C(O)OR⁷,—R⁸—C(O)N(R⁷)₂, —R⁸—N(R⁹)C(O)OR⁹, —R⁸—N(R⁹)C(O)R⁹, —R⁸—N(R⁹)(S(O)_(t)R⁹)(where t is 1 to 2), —R⁸—S(O)_(p)OR⁹ (where p is 1 to 2), —R⁸—S(O)_(t)R⁹(where t is 0 to 2), and —R⁸—S(O)_(P) N(R⁹)₂ (where p is 1 to 2) whereeach R⁷, R⁸ and R⁹ is as defined above in the Summary of the Invention.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above and R_(b) is one or more aryl radicalsas defined above, e.g., benzyl, diphenylmethyl and the like. The arylradical(s) may be optionally substituted as described above.

“Aralkenyl” refers to a radical of the formula —R_(c)R_(b) where R_(c)is an alkenyl radical as defined above and R_(b) is one or more arylradicals as defined above, which may be optionally substituted asdescribed above.

“Alkylene” and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain, linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to seven carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain may be attachedto the rest of the molecule and to the radical group can be through anytwo carbons within the chain.

“Alkenylene” and “alkenylene chain” refer to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to seven carbon atoms, e.g., ethenylene,propenylene, n-butenylene, and the like. The alkenylene chain isattached to the rest of the molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkenylene chain to the rest of the molecule and tothe radical group can be through any two carbons within the chain.

“Alkylidene” refers to a straight or branched hydrocarbon radical groupconsisting solely of carbon and hydrogen, containing at least one doublebond, having from one to seven carbon atoms, and that is attached to therest of the molecule through a double bond, e.g., methylene, ethylidene,propylidene, n-butylidene, and the like.

“Cycloalkyl” refers to a stable monocyclic or bicyclic hydrocarbonradical consisting solely of carbon and hydrogen atoms, having fromthree to ten carbon atoms, and which is saturated and attached to therest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise statedspecifically in the specification, the term “cycloalkyl” is meant toinclude cycloalkyl radicals which are optionally substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,—R⁸—OR⁷, —R⁸—N(R⁷)₂, —R⁸—C(O)R⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂,—R⁸—N(R⁹)C(O)OR⁹, —R⁸—N(R⁹)C(O)R⁹, —R⁸—N(R⁹)(S(O)_(t)R⁹) (where t is 1to 2), —R⁸—S(O)_(p)OR⁹ (where p is 1 to 2), —R⁸—S(O)_(t)R⁹ (where t is 0to 2), and —R⁸—S(O)_(p)N(R⁹)₂ (where p is 1 to 2) where each R⁷, R⁸ andR⁹ is as defined above in the Summary of the Invention.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The alkyl radical and the cycloalkyl radicalmay be optionally substituted as defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,2-bromoethenyl, 3-bromoprop-1-enyl, and the like.

“Haloalkylidene” refers to an alkylidene radical, as defined above, thatis substituted by one or more halo radicals, as defined above, e.g.,difluoromethylene, dichloromethylene, and the like.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur. Forpurposes of this invention, the heterocyclyl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated. Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.Unless stated otherwise specifically in the specification, the term“heterocyclyl” is meant to include heterocyclyl radicals as definedabove which are optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, —R⁸—OR⁷, —R⁸—N(R⁷)₂, —R⁸—C(O)R⁷,—R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—N(R⁹)C(O)OR⁹, —R⁸—N(R⁹)C(O)R⁹,—R⁸—N(R⁹)(S(O)_(t)R⁹) (where t is 1 to 2), —R⁸—S(O)_(p)OR⁹ (where p is 1to 2), —R⁸—S(O)_(t)R⁹ (where t is 0 to 2), and —R⁸—S(O)_(p)N(R⁹)₂ (wherep is 1 to 2) where each R⁷, R⁸ and R⁹ is as defined above in the Summaryof the Invention.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e) whereR_(a) is an alkyl radical as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The heterocyclyl radical may beoptionally substituted as defined above.

“Heteroaryl” refers to a 3- to 18-membered aromatic ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. For purposes ofthis invention, the heterocyclyl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized. Examples include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl,benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl,indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl,naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl,isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl. Unless stated otherwise specifically in thespecification, the term “heteroaryl” is meant to include heteroarylradicals as defined above which are optionally substituted by one ormore substituents selected from the group consisting of alkyl, alkenyl,halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, —R⁸—OR⁷, —R⁸—N(R⁷)₂,—R⁸—C(O)R⁷, —R⁸—C(O)OR⁷, —R⁸—C(O)N(R⁷)₂, —R⁸—N(R⁹)C(O)OR⁹,—R⁸—N(R⁹)C(O)R⁹, —R⁸—N(R⁹)(S(O)_(t)R⁹) (where t is 1 to 2),—R⁸—S(O)_(p)OR⁹ (where p is 1 to 2), —R⁸—S(O)_(t)R⁹ (where t is 0 to 2),and —R⁸—S(O)_(p)N(R⁹)₂ (where p is 1 to 2) where each R⁷, R⁸ and R⁹ isas defined above in the Summary of the Invention.

“Heteroarylalkyl” refers to a radical of the formula —R_(a)R_(f) whereR_(a) is an alkyl radical as defined above and R_(f) is a heteroarylradical as defined above. The heteroaryl radical may be optionallysubstituted as defined above.

“Heteroarylalkenyl” refers to a radical of the formula —R_(b)R_(f) whereR_(b) is an alkenyl radical as defined above and R_(f) is a heteroarylradical as defined above. The heteroaryl radical may be optionallysubstituted as defined above.

As used herein, compounds which are “commercially available” may beobtained from standard commercial sources including Acros Organics(Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis.; including SigmaChemical and Fluka), American Tissue Culture Collection (ATCC,Rockville, Md.), Apin Chemicals Ltd. (Milton Park UK), Avocado Research(Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Comwall, U.K.),Chemservice Inc. (West Chester Pa.), Crescent Chemical Co. (HauppaugeN.Y.), Eastman Organic Chemicals, Eastman Kodak Company (RochesterN.Y.), EM Industries, Inc. (Hawthorne, N.Y.; World Wide Web), FisherScientific Co. (Pittsburgh Pa.), Fisher Scientific Co. (Hampton, N.H.),Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan Utah),ICN Biomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.; www.lancaster.co.uk), MaybridgeChemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem Utah),Pfaltz & Bauer, Inc. (Waterbury Conn.), Polyorganix (Houston Tex.),Pierce Chemical Co. (Rockford Ill.), Praxair (Vancouver, B.C.), Riedelde Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (NewBrunswick, N.J.), Steraloids Inc. (Newport, R.I.), TCI America (PortlandOreg.), Trans World Chemicals, Inc. (Rockville Md.), and Wako ChemicalsUSA, Inc. (Richmond Va.).

As used herein, “suitable conditions” for carrying out a synthetic stepare explicitly provided herein or may be discerned by reference topublications directed to methods used in synthetic organic chemistry.The reference books and treatise set forth above that detail thesynthesis of reactants useful in the preparation of compounds of thepresent invention, will also provide suitable conditions for carryingout a synthetic step according to the present invention.

As used herein, “methods known to one of ordinary skill in the art” maybe identified through various reference books and databases. Suitablereference books and treatise that detail the synthesis of reactantsuseful in the preparation of compounds of the present invention, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Specificand analogous reactants may also be identified through the indices ofknown chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the present invention is P. H. Stahl & C. G.Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica ChimicaActa, Zurich, 2002.

As used herein, the term C₁₋₃₀ organic moiety refers to a stablearrangement of atoms composed of at least one and not more than aboutthe maximum carbon number set forth in the range, typically not morethan about 30 carbon atoms, and any number of non-carbon atoms.

The C₁₋₃₀ organic moiety may be a saturated or unsaturated hydrocarbylradical. A saturated hydrocarbyl radical is defined according to thepresent invention as any radical composed exclusively of carbon andhydrogen, where single bonds are exclusively used to join carbon atomstogether. Thus, any stable arrangement of carbon and hydrogen atoms,having at least one carbon atom, is included within the scope of asaturated hydrocarbon radical according to the invention. Some specificterminology that may be used to refer to specific carbon atomarrangements will be discussed below.

The carbon atoms may form an alkyl group as defined herein. The carbonatoms may form a cycloalkyl group as defined herein. Additional groupswithin the scope of “cycloalkyl” as defined herein are polycycloalkylgroups, defined below.

A polycycloalkyl group is an arrangement of carbon atoms wherein atleast one carbon atom is a part of at least two separately identifiablerings. The polycycloalkyl group may contain bridging between two carbonatoms, where bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl,bicyclo[5.2.0]nonyl, tricycl[2.2.1.0¹]heptyl, norbornyl and pinanyl arerepresentative examples. The polycycloalkyl group may contain one ormore fused ring systems, where decalinyl (radical from decalin) andperhydroanthracenyl are representative examples. The polycycloalkylgroup may contain a spiro union, in which a single atom is the onlycommon member of two rings. Spiro[3.4]octyl, spiro[3.3]heptyl andspiro[4.5]decyl are representative examples.

In addition, the saturated hydrocarbyl radical can be composed of anycombination of two or more of the above, i.e., any combination of alkyland cycloalkyl groups. Thus, the C₁₋₃₀ organic moiety may be an alkylgroup (e.g., methyl) with a cycloalkyl (e.g., cyclohexyl) substituent,so that C₁₋₃₀ organic moiety is a cyclohexylmethyl group. As anotherexample, the C₁₋₃₀ organic moiety may be a cycloalkyl group (e.g.,cyclooctyl) having two alkyl substituents (e.g., a methyl and ethylsubstituent), so that the C₁₋₃₀ organic moiety is amethylethylcyclooctyl group. As a final example, the C₁₋₃₀ organicmoiety may be a cycloalkyl group with an alkyl substituent, where thealkyl substituent is substituted with a polycycloalkyl substituent.

As indicated above, the C₁₋₃₀ organic moiety may be an unsaturatedhydrocarbyl radical. Such an C₁₋₃₀ organic moiety is defined as having acarbon arrangement as set forth above for saturated hydrocarbylradicals, with the additional feature that at least one bond between anytwo carbon atoms is other than a single bond. An alkyl group containingat least one single double bond is referred to herein as an alkenylgroup. An alkyl group containing at least one triple bond is referredherein to as an alkynyl group.

Likewise, the cycloalkyl group may have one or more double or triplebonds, and be included within the scope of an unsaturated hydrocarbylradical according to the invention. Cycloalkenyl and cycloalkynyl aregeneral names given to groups having a single carbon-based ring with asingle double and triple bond in the ring, respectively. Cycloalkadienylgroups are cycloalkyl groups with two double bonds contained in the ringstructure. The double bond may be exocyclic to the ring, e.g., a carbonatom of the ring may have a ═CH₂ group (i.e., a methylidene group) orhigher homologue bonded to it.

A ring may be unsaturated to the extent of being aromatic, and still beincluded within the scope of an unsaturated hydrocarbyl radical. Thus,an aryl group as defined herein is included within the scope of suchhydrocarbyl groups. As any combination of the above is also includedwithin the scope of an unsaturated hydrocarbyl radical, aralkyl (C₁₋₃₀organic moiety is an alkyl group with at least one aryl substituent,e.g., benzyl) and alkylaryl (C₁₋₃₀ organic moiety is an aryl ring withat least one alkyl substituent, e.g., tolyl) groups are included withinthe scope of C₁₋₃₀ organic moiety. C₆ aryls are a preferred component oforganic moieties of the invention.

Also included within the scope of an C₁₋₃₀ organic moiety are thoseorganic moieties that contain one or more heteroatoms. Heteroatomsaccording to the invention are any atom other than carbon and hydrogen.A preferred class of heteroatoms are naturally occurring atoms (otherthan carbon and hydrogen). Another preferred class are non-metallic(other than carbon and hydrogen). Another preferred class consists ofboron, nitrogen, oxygen, phosphorous, sulfur, selenium and halogen(i.e., fluorine, chlorine, bromine and iodine, with fluorine andchlorine being preferred). Another preferred class consists of nitrogen,oxygen, sulfur and halogen. Another preferred class consists ofnitrogen, oxygen and sulfur. Oxygen is a preferred heteroatom. Nitrogenis a preferred heteroatom.

For example, the C₁₋₃₀ organic moiety may be a hydrocarbyl radical asdefined above, with at least one substituent containing at least oneheteroatom. In other words, the C₁₋₃₀ organic moiety may be ahydrocarbyl radical as defined above, wherein at least one hydrogen atomis replaced with a heteroatom. For example, if the heteroatom is oxygen,the substituent may be a carbonyl group, i.e., two hydrogens on a singlecarbon atom are replaced by an oxygen, to form either a ketone oraldehyde group. Alternatively, one hydrogen may be replaced by an oxygenatom, in the form of an hydroxy, alkoxy, aryloxy, aralkyloxy,alkylaryloxy (where alkoxy, aryloxy, aralkyloxy, alkylaryloxy may becollectively referred to as hydrocarbyloxy), heteroaryloxy, —OC(O)R,ketal, acetal, hemiketal, hemiacetal, epoxy and —OSO₃M. The heteroatommay be a halogen. The heteroatom may be a nitrogen, where the nitrogenforms part of an amino (—NH₂, —NHR, —N(R)₂), alkylamido, arylamido,arylalkylamido, alkylarylamido, nitro, —N(R)SO₃M or aminocarbonylamidegroup. The heteroatom may be a sulfur, where the sulfur forms part of athiol, thiocarbonyl, —SO₃M, sulfonyl, sulfonamide or sulfonhydrazidegroup. The heteroatom may be part of a carbon-containing substituentsuch as formyl, cyano, —C(O)OH, —C(O)OR, —C(O)OM, —C(O)R, —C(O)N(R)₂,carbamate, carbohydrazide and carbohydroxamic acid.

In the above exemplary heteroatom-containing substituents, R representsthe remainder of the C₁₋₃₀ organic moiety and M represents proton or ametal ion. Preferred metal ions, in combination with a counterion, formphysiologically tolerated salts. A preferred metal from which a metalion may be formed include an alkali metal [for example, lithium (Li),sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs)] an alkalineearth metal (for example, magnesium (Mg), calcium (Ca) and strontium(Sr)], or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag). An alkalimetal or an alkaline earth metal are preferred M groups. Sodium,potassium, magnesium and calcium are preferred M groups. Sodium andpotassium are preferred M groups.

Another class of C₁₋₃₀ organic moieties according to the invention arehydrocarbyl radicals as defined above, wherein at least one heteroatomis substituted for a carbon atom in the hydrocarbyl. One example of suchorganic moieties is the heterocyclyls defined herein. Another example ofsuch organic moieties have a heteroatom bridging (a) the radical towhich the organic moiety is bonded and (b) the remainder of the organicmoiety. Examples include alkoxy, aryloxy, aralkoxy and alkylaryloxyradicals, which may collectively be referred to herein as hydrocarbyloxyradicals or moieties. Thus, —OR is an exemplary C₁₋₃₀ organic moiety ofthe invention (where R is the remainder of the C₁₋₃₀ organic moiety).Another example is —NHR (where R is the remainder of the C₁₋₃₀ organicmoiety). Other examples include —R⁸—OR⁷ and —R⁸—N(R⁷)₂ where R⁷ and R⁸are as defined above in the Summary of the Invention and R¹⁰ is a bondor a straight or branched alkylene or alkenylene chain.

While the C₁₋₃₀ organic moiety may have up to about 30 carbon atoms,preferred organic moieties of the invention have fewer than 30 carbonatoms, for example, up to about 25 carbon atoms, more preferably up toabout 20 carbon atoms. The organic moiety may have up to about 15 carbonatoms, or up to about 12 or 10 carbon atoms. A preferred category oforganic moieties has up to about 8 or 6 carbon atoms.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Oxygen protecting group” refers to a radical which protects andmaintains a hydroxy group during subsequent chemical reactions. Suchgroups include, but are not limited to, trialkylsilyl ordiarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Protectinggroups may be added or removed in accordance with standard techniques,which are well-known to those skilled in the art and as describedherein. The use of protecting groups, particularly oxygen protectinggroups, is described in detail in Green, T. W. and P. G. M. Wutz,Protective Groups in Organic Synthesis (1991), 2nd Ed.,Wiley-Interscience.

“Leaving group initiator” refers to a radical which, together with theoxygen to which is it attached, forms a leaving group which is easilyremoved from the rest of the molecule upon attack by the appropriatenucleophile. The hydroxy radical is not a good leaving group and musttherefore be converted to a group that does leave. One way is toprotonate the hydroxy radical (to form a more acidic leaving group).Another is to convert the hydroxy to a reactive ester, most commonly, toa sulfonic ester. The sulfonic ester groups tosylate, brosylate,nosylate and mesylate are frequently used. Other leaving groups includeoxonium ions, alkyl perchorates, ammonioalkanesulfonate esters, alkylfluorosulfonates and the fluorinated compounds triflates and nonaflates.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid,alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, camphoric acid,camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid,carbonic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid,glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoricacid, glycolic acid, hippuric acid, isobutyric acid, lactic acid,lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid,mandelic acid, methanesulfonic acid, mucic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid,oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamicacid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid,stearic acid, succinic acid, tartaric acid, thiocyanic acid,p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and thelike.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, ofinflammatory disease in the mammal. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the condition and its severity, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or disorder of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment; or

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition.

Compounds of the invention have a central nucleus of three rings,designated herein as A, C, and D as shown below:

The carbons of the central nucleus are numbered as set forth above. Forpurposes herein, the carbon at position 1 of the central nucleus isindicated herein as C1, and so forth.

In the compounds of the invention, unless otherwise indicated, each ofrings A, C, and D is independently fully saturated, partially saturatedor fully unsaturated. That is, hydrogens attached to any of the carbonsat positions 1-5 and 8-17 may be omitted so as to allow unsaturationwithin the A, C and/or D rings. For example, when carbons at numerals 5,8, 9, 10, 13 and 14 are indicated as being substituted with onehydrogen, and it is also indicated that each of rings A, C and D isindependently fully saturated, partially saturated or fully unsaturated,then any one or more of the hydrogens attached to carbons at numerals 5,8, 9 and 14 may be omitted in order to allow unsaturation at the carbonatom.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as reverse phase HPLC. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

The nomenclature used herein for the compounds of the invention is amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds are named herein as derivatives of the indene moiety. Thelocant numbering of the various substituents off the indene ring in thenames of the compounds of the invention is based on the standard locantnumbering system for indene rings. In addition, the configuration of thesubstituents are indicated in the names of the compounds by an “α” ifthe substituent is below the plane of the indene ring and by a “β” isthe substituent is above the plane of the indene ring. For example, acompound of formula (Ia) (showing the numbering of the carbons:

where C1, C4, C11, C12, C15 and C16 are each independently substitutedwith two hydrogens; C9 and C14 are each independently substituted withhydrogen; R¹ is β-hydroxy; R² is (3-(2-hydroxyethyl); R³ is α-hydroxy;R^(4a) and R^(4b) together form methylene; R⁵ is 13-methyl; and R⁶ ishydrogen, i.e., a compound of the following formula:

is named herein as5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene.

The compounds of the invention may, and typically do, exist as solids,including crystalline solids which can be crystallized from commonsolvents such as ethanol, N,N-dimethylformamide, water, or the like ormixtures thereof. The crystallization process may, depending on thecrystallization conditions, provide various polymorphic structures.Typically, a more thermodynamically stable polymorph is advantageous tothe commercial scale manufacture of a steroid compound of the invention,and is a preferred form of the compound.

Often, crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more compounds of the invention with one or moremolecules of solvent. The solvent may be water, in which case thesolvate may be a hydrate. Alternatively, the solvent may be an organicsolvent. Thus, the compounds of the present invention may exist as ahydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate,trihydrate, tetrahydrate and the like, as well as the correspondingsolvated forms. The compound of the invention may be true solvates,while in other cases, the compound of the invention may merely retainadventitious water or solvent or a mixture of water and solvent.

As used herein, a “pharmaceutically acceptable solvate” refers to asolvate that retains the biological effectiveness and properties of thebiologically active compounds of the invention. Examples ofpharmaceutically acceptable solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, EtOAc, acetic acid, andethanolamine. It should be appreciated by those skilled in the art thatsolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Sykes, P. A.,Guidebook to Mechanism in Organic Chemistry, 6th Ed (1986, John Wiley &Sons, N.Y.) is an exemplary reference that describe solvates.

B. PHARMACEUTICAL COMPOSITIONS

The present invention provides a pharmaceutical or veterinarycomposition (hereinafter, collectively referred to as a pharmaceuticalcomposition) containing a compound of the invention as described above,in admixture with a pharmaceutically acceptable carrier. The inventionfurther provides a composition, preferably a pharmaceutical composition,containing an effective amount of a compound as described above, inassociation with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be in anyform which allows for the composition to be administered to a patient.For example, the composition may be in the form of a solid, liquid orgas (aerosol). Typical routes of administration include, withoutlimitation, oral, topical, parenteral, sublingual, rectal, vaginal,ocular, and intranasal. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. Pharmaceutical composition of theinvention are formulated so as to allow the active ingredients containedtherein to be bioavailable upon administration of the composition to apatient. Compositions that will be administered to a patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units.

Materials used in preparing the pharmaceutical compositions should bepharmaceutically pure and non-toxic in the amounts used. It will beevident to those of ordinary skill in the art that the optimal dosage ofthe active ingredient(s) in the pharmaceutical composition will dependon a variety of factors. Relevant factors include, without limitation,the type of subject (e.g., human), the particular form of the activeingredient, the manner of administration and the composition employed.

In general, the pharmaceutical composition includes an (where “a” and“an” refers here, and throughout this specification, as one or more)active compound of the invention as described herein, in admixture withone or more carriers. The carrier(s) may be particulate, so that thecompositions are, for example, in tablet or powder form. The carrier(s)may be liquid, with the compositions being, for example, an oral syrupor injectable liquid. In addition, the carrier(s) may be gaseous, so asto provide an aerosol composition useful in, e.g., inhalatoryadministration.

When intended for oral administration, the composition is preferably ineither solid or liquid form, where semi-solid, semi-liquid, suspensionand gel forms are included within the forms considered herein as eithersolid or liquid.

As a solid composition for oral administration, the composition may beformulated into a powder, granule, compressed tablet, pill, capsule,chewing gum, wafer or the like form. Such a solid composition willtypically contain one or more inert diluents or edible carriers. Inaddition, one or more of the following adjuvants may be present: binderssuch as carboxymethylcellulose, ethyl cellulose, microcrystallinecellulose, or gelatin; excipients such as starch, lactose or dextrins,disintegrating agents such as alginic acid, sodium alginate, Primogel,corn starch and the like; lubricants such as magnesium stearate orSterotex; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin, a flavoring agent such as peppermint,methyl salicylate or orange flavoring, and a coloring agent.

When the composition is in the form of a capsule, e.g., a gelatincapsule, it may contain, in addition to materials of the above type, aliquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.

The composition may be in the form of a liquid, e.g., an elixir, syrup,solution, emulsion or suspension. The liquid may be for oraladministration or for delivery by injection, as two examples. Whenintended for oral administration, preferred composition contain, inaddition to the present compounds, one or more of a sweetening agent,preservatives, dye/colorant and flavor enhancer. In a compositionintended to be administered by injection, one or more of a surfactant,preservative, wetting agent, dispersing agent, suspending agent, buffer,stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, cyclodextrin, propylene glycol or othersolvents; antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid composition intended for either parenteral or oraladministration should contain an amount of a compound of the inventionsuch that a suitable dosage will be obtained. Typically, this amount isat least 0.01% of a compound of the invention in the composition. Whenintended for oral administration, this amount may be varied to bebetween 0.1% and about 80% of the weight of the composition. Preferredoral compositions contain between about 4% and about 50% of the activecompound of the invention. Preferred compositions and preparationsaccording to the present invention are prepared so that a parenteraldosage unit contains between 0.01% to 2% by weight of active compound.

The pharmaceutical composition may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, beeswax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of formula the invention of from about0.01% to about 10% w/v (weight per unit volume).

The composition may be intended for rectal administration, in the form,e.g., of a suppository which will melt in the rectum and release thedrug. The composition for rectal administration may contain anoleaginous base as a suitable nonirritating excipient. Such basesinclude, without limitation, lanolin, cocoa butter and polyethyleneglycol.

The composition may include various materials which modify the physicalform of a solid or liquid dosage unit. For example, the composition mayinclude materials that form a coating shell around the activeingredients. The materials which form the coating shell are typicallyinert, and may be selected from, for example, sugar, shellac, and otherenteric coating agents. Alternatively, the active ingredients may beencased in a gelatin capsule.

The composition in solid or liquid form may include an agent which bindsto the active component(s) and thereby assists in the delivery of theactive components. Suitable agents which may act in this capacityinclude a monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the present invention may consist ofgaseous dosage units, e.g., it may be in the form of an aerosol. Theterm aerosol is used to denote a variety of systems ranging from thoseof colloidal nature to systems consisting of pressurized packages.Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem which dispenses the active ingredients. Aerosols of compounds ofthe invention may be delivered in single phase, bi-phasic, or tri-phasicsystems in order to deliver the active ingredient(s). Delivery of theaerosol includes the necessary container, activators, valves,subcontainers, spacers and the like, which together may form a kit.Preferred aerosols may be determined by one skilled in the art, withoutundue experimentation.

Whether in solid, liquid or gaseous form, the pharmaceutical compositionof the present invention may contain one or more known pharmacologicalagents used in the treatment of inflammation (including asthma, allergy,rheumatoid arthritis, multiple sclerosis, etc.), autoimmune diseases(including diabetes and lupus erythematosus), and proliferativedisorders (cancers).

The pharmaceutical compositions may be prepared by methodology wellknown in the pharmaceutical art.

A composition intended to be administered by injection can be preparedby combining the compound of the invention with water so as to form asolution. A surfactant may be added to facilitate the formation of ahomogeneous solution or suspension. Surfactants are compounds thatnon-covalently interact with the compound of the invention so as tofacilitate dissolution or homogeneous suspension of the active compoundin the aqueous delivery system.

C. METHODS OF USE

The compounds of the invention, or pharmaceutical compositionscomprising one of more of these compounds and a pharmaceuticallyacceptable carrier, diluent or excipient, may be used in a method fortreating or preventing an inflammatory condition or disease in apatient, where the method comprises administering to the patient in needthereof an amount of a compound or composition according to the presentinvention, where the amount is effective to treat or prevent theinflammatory condition or disease of the patient.

The inflammatory condition or disease may involve acute or chronicinflammation of bone and/or cartilage of joints; the inflammatorycondition or disease may be an arthritis selected from rheumatoidarthritis, gouty arthritis or juvenile rheumatoid arthritis; theinflammatory condition may be an autoimmune condition or disease; theinflammatory condition or disease may involve central nervous systeminflammation (e.g., wherein the central nervous system disease ismultiple sclerosis, or wherein the central nervous system disease isAlzheimer's); the inflammatory condition or disease may be lupuserythematosus disease; the inflammatory condition or disease may be aninflammatory bowel disease (e.g., Crohn's disease or ulcerativecolitis); the inflammatory condition or disease may be an inflammatorycutaneous disease (e.g., psoriasis or dermatitis); the inflammatorycondition or disease may be graft vs host disease; the inflammatorycondition or disease may be vascular (e.g., vasculitis); theinflammatory condition or disease may be an atherosclerotic disease; theinflammatory condition or disease may involve respiratory inflammation(e.g., wherein the respiratory disease is asthma, or wherein therespiratory disease is chronic obstructive pulmonary disease; or whereinthe respiratory disease is emphysema); the inflammatory condition ordisease may be pulmonary sarcadosis; the inflammatory condition ordisease may be ocular inflammation or allergy; the inflammatorycondition or disease may be allergic rhinitis; the condition or diseasemay be associated with leukocyte infiltration; the condition or diseasemay be associated with edema; the condition or disease may be associatedwith ischemia reperfusion injury; the condition or disease may beassociated with elevated levels of inflammatory cytokines (e.g., whereinthe inflammatory cytokine is IL-1, or wherein the inflammatory cytokineis IL-2, or wherein the inflammatory cytokine is IL-3, or wherein theinflammatory cytokine is interleukin (IL)-4, or wherein the inflammatorycytokine is IL-5, or wherein the inflammatory cytokine is IL-6, orwherein the inflammatory cytokine is IL-8, or wherein the inflammatorycytokine is IL-9, or wherein the inflammatory cytokine is IL-10, orwherein the inflammatory cytokine is IL-12, or wherein the inflammatorycytokine is IL-13, or wherein the inflammatory cytokine is IL-18, orwherein the inflammatory cytokine is TNF-α, or wherein the inflammatorycytokine is TGF-β, or wherein the inflammatory cytokine is GM-CSF, orwherein the inflammatory cytokine is IFN-γ, or wherein the inflammatorycytokine is LTB4, or wherein the inflammatory cytokine is a member ofthe cysteinyl leukotriene family, or wherein the inflammatory cytokineis regulated on activation normal T cell expressed and secreted(RANTES), or wherein the inflammatory cytokine is eotaxin-1, 2, or 3, orwherein the inflammatory cytokine is macrophage inflammatory protein(MIP)-1α, or wherein the inflammatory cytokine is monocytechemoattractant protein-1, 2, 3, or 4); the condition or disease may beassociated with altered levels of inflammatory adhesion molecules (e.g.,wherein the adhesion molecule is an immunoglobulin such as vascular celladhesion molecule (VCAM-1 or 2) or intercellular adhesion molecule(ICAM-1 or 2); wherein the adhesion molecule is an integrin such as verylate antigen-4 (VLA-4) or Mac-1; wherein the adhesion molecule is aselectin such as e-selectin).

Furthermore, the present invention provides a method for treating orpreventing a disease or condition in a patient, where the disease orcondition is associated with pathological conditions that involveleukocyte infiltration, the method comprising administering to a patientin need thereof an amount of a compound or a composition of the presentinvention, wherein the amount is effective to treat or prevent a diseaseor condition associated with pathological conditions that involveleukocyte infiltration.

Furthermore, the present invention provides a method of treating orpreventing arthritis in a patient, comprising administering to a patientin need thereof an amount of a compound or composition of the presentinvention, where the amount is effective to treat or prevent arthritisin the patient.

Furthermore, the present invention provides a method of treating orpreventing inflammatory bowel disease in a patient, comprisingadministering to a patient in need thereof an amount of a compound orcomposition of the present invention, where the amount is effective totreat or prevent inflammatory bowel disease in the patient.

Furthermore, the present invention provides a method of treating orpreventing inflammatory bowel disease in a patient, comprisingadministering to a patient in need thereof an amount of a compound orcomposition of the present invention, where the amount is effective totreat or prevent psoriasis in the patient.

Furthermore, the present invention provides a method of treating orpreventing atherosclerosis in a patient, comprising administering to apatient in need thereof an amount of a compound or composition of thepresent invention, where the amount is effective to treat or preventatherosclerosis in the patient.

In a method of the present invention, a compound of the invention, or apharmaceutical composition comprising one or more compounds of theinvention and a pharmaceutically acceptable carrier, diluent orexcipient, may, although need not, achieve one or more of the followingdesired results in the subject to whom has been administered a compoundof the invention as defined above, or a composition containing one ofthese compounds and a pharmaceutically acceptable carrier, diluent orexcipient:

-   -   1. Inhibition of leukocyte infiltration (e.g., neutrophils,        macrophages, etc.)    -   2. Inhibition of leukocyte activation    -   3. Alteration of lymphocyte ratio (e.g., TH1 vs TH2 cells)    -   4. Inhibition of leukocyte chemotaxis;    -   5. Inhibition of TNF-α production and/or release;    -   6. Inhibition of chemokine production and/or release (e.g.,        eotaxin, etc.);    -   7. Inhibition of adhesion molecule production, release and/or        function (e.g. VCAM, VLA-4, etc.);    -   8. Inhibition of edema;    -   9. Inhibition of interleukin cytokine production and/or release        (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL6, IL-8, IL-9, IL10,        IL-12, IL-13, IL-18);    -   10. Inhibition of inflammatory mediator release (e.g.,        leukotrienes, tryptase, adenosine etc.);    -   11. Inhibition of parameters of arthritis;    -   12. Inhibition of parameters of inflammatory bowel disease;    -   13. Inhibition of parameters of psoriasis;    -   14. Inhibition of parameters of atherosclerosis.

The compounds of the invention disclosed herein or pharmaceutical orcompositions comprising one of more of these compounds and apharmaceutically acceptable carrier, diluent or excipient, may be usedin a method for treating or preventing a proliferative disorder in apatient, where the method comprises administering to the patient in needthereof an amount of a compound or composition according to the presentinvention, where the amount is effective to treat or prevent theproliferative disorder of the patient. As used herein, proliferativedisorders includes, without limitation, all leukemias and solid tumorsthat are susceptible to undergoing differentiation or apoptosis uponinterruption of their cell cycle.

Thus, the inventive method may be used to treat inflammation, includingboth acute and chronic inflammation, as well as certain proliferativedisorders (cancers). As used herein, inflammation includes, withoutlimitation, arthritis (where this term encompasses over 100 kinds ofdiseases, including rheumatoid arthritis, psoriatic arthritis,ankylosing spondylitis, osteoarthritis, gout, and synovitis),inflammations of the brain (including multiple sclerosis, Alzheimer's,AIDS dementia, stroke, encephalitis, trauma, and Creutzfeld-Jakobdisease), inflammatory bowel disease (including Crohn's disease andulcerative colitis), irritable bowel syndrome, ischemia-reperfusioninjury including myocardial infarction, sarcoidosis, psoriasis,tissue/organ transplant, graft vs host disease, systemic lupuserythematosus, Type I juvenile diabetes, vasculitis, artherosclerosis,cardiomyopathy, autoimmune myocarditis, atopic dermatitis, asthma,allergy, allergic rhinitis, and chronic obstructive pulmonary disease(including emphysema and bronchitis).

The inventive method provides for administering a therapeuticallyeffective amount of a compound of the invention, including salts,compositions etc. thereof. As used herein, the actual amount encompassedby the term “therapeutically effective amount” will depend on the routeof administration, the type of warm-blooded animal being treated, andthe physical characteristics of the specific warm-blooded animal underconsideration. These factors and their relationship to determining thisamount are well known to skilled practitioners in the medical arts. Thisamount and the method of administration can be tailored to achieveoptimal efficacy but will depend on such factors as weight, diet,concurrent medication and other factors that those skilled in themedical arts will recognize.

A therapeutically effective amount of a compound or pharmaceuticalcomposition of the present invention will be sufficient to treatinflammation or proliferative diseases in a warm-blooded animal, such asa human. Methods of administering therapeutically effective amounts ofanti-inflammatory agents are well known in the art and include theadministration of inhalation, oral or parenteral forms. Such dosageforms include, but are not limited to, parenteral solutions, tablets,capsules, sustained release implants and transdermal delivery systems;or inhalation dosage systems employing dry powder inhalers orpressurized multi-dose inhalation devices.

The dosage amount and frequency are selected to create a therapeuticallyeffective level of the agent without harmful effects. It will generallyrange from a dosage of about 0.001 to 100 mg/Kg/day, and typically fromabout 0.01 to 10 mg/Kg/day where administered orally or intravenously.Also, the dosage range will be typically from about 0.0001 to 10mg/Kg/day where administered intranasally or by inhalation.

D. PREFERRED EMBODIMENTS OF THE INVENTION

Of the compounds of formula (I) set forth above in the Summary of theInvention, a preferred group of compounds are those compounds of formula(Ia):

wherein:

the A, C or D ring is independently fully saturated or partiallysaturated;

C1, C4, C11, C12, C15 and C16 are each independently substituted withtwo hydrogens;

C9 and C14 are each independently substituted with hydrogen;

R¹ is —OR⁷ or —N(R⁷)₂;

R² and R³ are each independently selected from the group consisting of—R⁸—OR⁷, —R⁸—OC(O)R⁹, —R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹,—R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of this group of compounds, one preferred subgroup of compounds is thesubgroup wherein:

R¹ is —OR⁷;

R² and R³ are each independently selected from the group consisting of—R⁸—OR⁷, —R⁸—OC(O)R⁹, —R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹,—R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of this subgroup of compounds, one preferred class of compounds is thatclass wherein:

R¹ is —OR⁷;

R² is —R⁸—OR⁷;

R³ is selected from the group consisting of —R⁸—OR⁷, —R⁸—OC(O)R⁹,—R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹, —R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2),—R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of this class of compounds, one preferred subclass of compounds is thatsubclass wherein:

R¹ is —OR⁷;

R² is —R⁸—OR⁷;

R³ is —R⁸—OR⁷;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl;

R⁶ is hydrogen;

each R⁷ is independently selected from the group consisting of hydrogen,alkyl, substituted aryl or optionally substituted aralkyl; and

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain.

Of this class of compounds, another preferred subclass of compounds isthat subclass wherein:

R¹ is —OR⁷;

R² is —R⁸—OR⁷;

R³ is —R¹⁰—N(R⁷)₂;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of the preferred subgroup described above, another preferred class ofcompounds is that class wherein:

R¹ is —OR⁷;

R² is —R¹⁰—N(R⁷)₂;

R³ is selected from the group consisting of —R⁸—OR⁷, —R⁸—OC(O)R⁹,—R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹, —R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2),—R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of this preferred class of compounds, one preferred subclass ofcompounds is that subclass wherein:

R¹ is —OR⁷;

R² is —R¹⁰—N(R⁷)₂;

R³ is —R⁸—OR⁷;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of this preferred class of compounds, another preferred subclass ofcompounds is that subclass wherein:

R¹ is —OR⁷;

R² is —R¹⁰—N(R⁷)₂;

R³ is —R¹⁰—N(R⁷)₂;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16; or R^(4a) and R^(4b) together form alkylideneor haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of the group of compound first described above, another preferredsubgroup of compounds is that subgroup wherein:

R¹ is —N(R⁷)₂;

R² and R³ are each independently selected from the group consisting of—R⁸—OR⁷, —R⁸—OC(O)R⁹, —R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹,—R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of the preferred class of compounds first described above, anotherpreferred subclass of compounds is that subclass wherein:

R¹ is —OR⁷;

R² is —R⁸—OR⁷;

R³ is —R¹⁰—N(R⁹)C(O)R⁹, —R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2) or—R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of the preferred subgroup of compounds first described above, anotherpreferred class of compounds is that class wherein:

R¹ is —OR⁷;

R² is selected from the group consisting of —R⁸—OC(O)R⁹,—R¹⁰—N(R⁹)C(O)R⁹, —R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2),—R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkenyl;

R³ is —R⁸—OR⁷ or —R⁸—OC(O)R⁹;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of the preferred class of compounds first described above, anothersubclass of compounds is that subclass wherein:

R¹ is —OR⁷;

R² is —R⁸—OR⁷;

R³ is heterocyclylalkyl, optionally substituted heteroarylalkyl,optionally substituted heteroarylalkenyl or optionally substitutedheteroarylalkenyl;

R^(4a) and R^(4b) are each independently selected from hydrogen, alkyl,alkenyl or alkynyl;

or R^(4a) is hydrogen, alkyl, alkenyl or alkynyl and R^(4b) is a directbond to the carbon at C16;

or R^(4a) and R^(4b) together form alkylidene or haloalkylidene;

R⁵ is alkyl or R⁵ is a direct bond to the carbon at C14;

R⁶ is hydrogen, —R⁸—OR⁷ or —R⁸—N(R⁷)₂;

each R⁷ is independently selected from the group consisting of hydrogen,—R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl;

each R⁸ is independently selected from the group consisting of a directbond, a straight or branched alkylene chain, and a straight or branchedalkenylene chain; and

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl;

each R¹⁰ is independently selected from the group consisting of astraight or branched alkylene and a straight or branched alkenylenechain.

Of the preferred groups of compounds set forth above, the most preferredcompounds of the invention are those compounds which are disclosed belowin the “Synthesis Examples”. Of the preferred groups of compounds setforth above, the most preferred R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷,R⁸, R⁹ and R¹⁰ selections may be discerned from the compounds which aredisclosed below in the “Synthesis Examples”. For example, the mostpreferred selection for R^(4a) and R^(4b) is when they together form amethylene or an ethylidene group. For example, a preferred selection forR¹ is —R⁸—OR⁷ where R⁸ is a direct bond and R⁷ is hydrogen. For example,a preferred selection for R⁵ is methyl. For example, a preferredselection for R⁶ is hydrogen. Similar preferred embodiments are readilydiscernible by the following disclosure and the attached claims.

Of the methods of treating an inflammatory condition or disease in amammal by administering a compound of the invention, as set forth abovein the Summary of the Invention, a preferred method administers acompound of formula (Ia). In addition, a preferred method is one whereinthe inflammatory condition or disease is selected from the following:

arthritis (including rheumatoid arthritis, psoriatic arthritis,ankylosing spondylitis, osteoarthritis, gout, and synovitis),inflammations of the brain (including multiple sclerosis, Alzheimer's,AIDS dementia, stroke, encephalitis, trauma, and Creutzfeld-Jakobdisease), inflammatory bowel disease (including Crohn's disease andulcerative colitis), irritable bowel syndrome, ischemia-reperfusioninjury (including myocardial infarction), sarcoidosis, psoriasis,tissue/organ transplant, graft vs host disease, systemic lupuserythematosus, Type I juvenile diabetes, vasculitis, artherosclerosis,cardiomyopathy, autoimmune myocarditis, atopic dermatitis, asthma,allergy, allergic rhinitis, and chronic obstructive pulmonary disease(including emphysema and bronchitis).

E. PREPARATION OF THE COMPOUNDS OF THE INVENTION

The compounds of the invention can be prepared by methods employingsteps known to those skilled in the art or analogous to those steps.General methods for the reactions on steroids can be found in “SteroidReactions”, C. Djerassi, Ed. Holden Day, San Francisco, Calif., 1963 andreferences cited therein. General synthetic methods can be found in“Comprehensive Organic Transformations”, R. C. Larock, VCH Publishers,New York, N.Y., 1989 and references cited therein. Additional literaturereferences useful for the synthesis of compounds of the invention are asfollows: T. Reichstein; C. H. Meystre, Helv. Chim. Acta, 1932, 22, 728;H. Westmijze; H. Kleyn; P. Vermeer; L. A. van Dijck, Tet. Lett. 1980,21, 2665; K. Prezewowsky; R Wiechert, U.S. Pat. No. 3,682,983; P.Kaspar; H. Witzel, J. Steroid Biochem. 1985, 23, 259; W. G. Dauben; T.Brookhart, J. Am. Chem. Soc. 1981, 103, 237; A. J. Manson et al., J.Med. Chem. 1963, 6, 1; R. O. Clinton et al, J. Am. Chem. Soc. 1961, 83,1478; M. S. Ahmad; L. A. Khan, Acta. Chim. Acad. Sci. Hung. 1981, 106,111.

In particular, compounds of the invention may be prepared by thefollowing Schemes or by the Reaction Schemes disclosed in the followingSynthesis Examples. It is understood that other compounds of theinvention may be prepared in a similar manner as described below or bymethods known to one of ordinary skill in the art. It is also understoodthat although the following Synthesis Examples may be directed to thepreparation of a specific substituent on a particular carbon in thecompounds, one of ordinary skill in the art would be able to preparesimilar substituents on other carbons of the compounds based on theteachings provided herein and in view of what is commonly known in theart.

Referring to the following Scheme A, ketones of compound 1, or compoundsanalogous thereto, can be alkylated with a variety of alkylating groupsto give compounds of the invention having but not limited to alkyl,cycloalkyl, aryl and heteroaryl substitution. Alkylation of the17-ketone 1 with the anion of acetylene generates the17α-ethynyl-17β-hydroxyl intermediate 2. Reversal of the stereochemistryof the C17 substituents may be carried out by first forming themethylsulfonate followed by treatment with silver (I) nitrate intetrahydrofuran (THF) and water. Dehydration of compound 2 using POCl₃in 2,4-lutidine gives compound 3. Treatment with tetrabutylammoniumfluoride removes the tert-butyldimethylsilyl groups to give compound 4.

Referring to the following Scheme B, compounds of the invention havingan allene functionality may be prepared from intermediates analogous tocompound 2. Exemplary is the reaction of compound 2 with LiAlH₄ andAlCl₃ in THF to give the allene 5. Treatment with tetrabutylammoniumfluoride removes the tert-butyldimethylsilyl groups to give compound 6.

Referring to the following Scheme C, compounds of the invention havingan alkynyl functionality may be prepared from allene intermediates.Exemplary is the treatment of compound 5 with n-BuLi in THF giving the17β-ethynyl compound 7.

Treatment with tetrabutylammonium fluoride removes thetert-butyldimethylsilyl groups to give compound 8.

Referring to the following Scheme D, compounds of the invention havingalkenyl functionality may be prepared from alkyne intermediates.Exemplary is the controlled hydrogenation of compound 7 using Pd—CaCO₃as catalyst to give the alkene 9. Treatment with tetrabutylammoniumfluoride removes the tert-butyldimethylsilyl groups to give compound 10.

Compound 1 can be used in a multitude of olefination reactions,including Wittig-type reactions to provide compounds of the inventionhaving an exocyclic olefin. For example, as illustrated in the followingScheme E, compound 1 may be treated with ethyltriphenylphosphoniumbromide and potassium tert-butoxide to provide compound having R₁=methyland R₂=hydrogen. Treatment with tetrabutylammonium fluoride removes thetert-butyldimethylsilyl groups to give compound 12.

In analogy to the synthesis shown in the following Scheme E, ketonessuch as compound 1 may be reacted with other Wittig-type reagents suchas, but not limited to, methyl-, propyl-, butyl-, pentyl- orhexyltriphenyl-phosphonium bromide to give compounds of the inventionanalogous to compound 12 having R₂=hydrogen and R₁=hydrogen, ethyl,propyl, butyl or pentyl.

Compounds of the invention can contain exocyclic double bonds of Eand/or Z geometry. For example, as illustrated in the following SchemeF, the Z-olefin 11 in cyclohexane may be treated with UV light in thepresence of diphenyl disulfide resulting in isomerization to theE-olefin 13. Treatment with tetrabutylammonium fluoride removes thetert-butyldimethylsilyl groups to give compound 14.

A multitude of compounds of the invention having functionalizedsidechains can be prepared using methods such as Lewis acid promotedcouplings to aldehydes and Michael acceptors. For example, asillustrated in the following Scheme G, compound 11 may be reacted withmethyl propiolate in the presence of diethylaluminum chloride to givecompound 15. The double bonds may be hydrogenated using a catalyst suchas platinum to give compound 16. Treatment with tetrabutylammoniumfluoride removes the tert-butyldimethylsilyl groups to give compound 17.

The following specific examples are provided as a guide to assist in thepractice of the invention, and are not intended as a limitation on thescope of the invention.

Unless otherwise stated, flash chromatography and column chromatographyused in the following examples may be accomplished using Merck silicagel 60 (230-400 mesh). Flash chromatography may be carried out accordingto the procedure set forth in: “Purification of Laboratory Chemicals”,3rd. edition, Butterworth-Heinemann Ltd., Oxford (1988), Eds. D. D.Perrin and W. L. F. Armarego, page 23. Column chromatography refers tothe process whereby the flow rate of eluent through a packing materialis determined by gravity. In all cases flash chromatography and radialchromatography may be used interchangeably. Radial chromatography may beperformed using silica gel on a Chromatotron Model #7924T (HarrisonResearch, Palo Alto, Calif.). Unless otherwise stated, quoted R_(f)values are obtained by thin layer chromatography using Silica Gel 60F₂₅₄ (Merck KGaA, 64271, Darmstadt, Germany). Brine refers to asaturated solution of sodium chloride.

Also, unless otherwise stated, chemical reactants and reagents wereobtained from standard chemical supply houses, such as Aldrich(Milwaukee, Wis.; www.aldrich.sial.com); EM Industries, Inc. (Hawthorne,N.Y.); Fisher Scientific Co. (Hampton, N.H.); and Lancaster Synthesis,Inc. (Windham, N.H.). Gases were obtained from Praxair (Vancouver,B.C.). Cell lines, unless otherwise stated, where obtained from publicor commercial sources, e.g., American Tissue Culture Collection (ATCC,Rockville, Md.).

SYNTHESIS EXAMPLES Example 1

Compound 25, a representative compound of the invention, may be preparedaccording to Reaction Scheme 1. Any number of compounds related tocompound 25 could be produced using similar methodology. Startingcompound 18 may be prepared according to the procedures outlined in U.S.Pat. No. 6,046,185.

In general, hydrogenation of compound 18 using Pd on carbon as catalystgives compound 19. Baeyer-Villager oxidation using 3-chloroperoxybenzoicacid (MCPBA) in CHCl₃ gives the lactone compound 20. Lithium aluminumhydride reduction of the lactone in THF gives the diol compound 21.Reaction of compound 21 with tert-butyldiphenylsilyl chloride (TBDPSCl)and imidazole in DMF protects the primary hydroxyl in compound 22.Treatment with 80% acetic acid removes the ketal and thetert-butyldimethylsilyl (TBS) group to give compound 23. Olefination ofcompound 23 using methyltriphenyl-phosphonium bromide and KO^(t)Bu inTHF gives the methylidene compound 24. Treatment with a refluxingsolution of Bu₄NF in THF removes the TBDPS group to give compound 25.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 19

A solution of compound 18 (2.03 g, 4.41 mmol) in EtOAc (135 mL) wastreated overnight with hydrogen (balloon pressure) in the presence of acatalytic amount of Pd on carbon. The catalyst was removed by filtrationand the solution was concentrated to dryness. The residue was purifiedby chromatography on silica gel (hexanes/EtOAc/CH₂Cl₂, 8:1:1) to givecompound 19 (1.79 g, 88%) as a white solid.

Synthesis of Compound 20

A mixture of compound 19 (2.38 g, 5.14 mmol) and MCPBA (3.11 g, 10.3mmol) in chloroform (26 mL) was refluxed for 4 hours. After cooling toambient temperature, the reaction mixture was diluted with EtOAc (25mL), washed with saturated Na₂SO₃ (2×20 mL), saturated NaHCO₃ (2×20 mL)and brine (2×20 mL) then dried over anhydrous MgSO₄, and concentrated todryness. The crude compound (2.43 g, white solid) was used for the nextreaction without further purification.

Synthesis of Compound 21

To a solution of compound 20 (1.00 g, 2.09 mmol) in THF at 0° C. wasadded LiAlH₄ (21 mL of a 1 M solution in THF, 2.09 mmol). The reactionmixture was stirred at ambient temperature for one hour then brine (5mL) was slowly added. The solution was extracted with CH₂Cl₂ (2×15 mL)then was dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel (EtOAc) to afford compound 21(0.786 g, 78%) as a white solid.

Synthesis of Compound 22

A solution of compound 21 (0.93 g, 1.93 mmol), TBDPSCl (1.1 mL, 4.4mmol) and imidazole (0.57 g, 8.5 mmol) in dry DMF (10 mL) was stirredovernight. The reaction mixture was diluted with EtOAc (50 mL) andwashed with brine (2×20 mL) then was dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc, 3:1) to afford compound 22 (1.22 g, 66%) as a whitesolid.

Synthesis of Compound 23

A mixture of compound 22 (1.00 g, 1.39 mmol) and 80% acetic acid (20mL)) was stirred at 50° C. for 2 hours then was diluted with toluene (30mL) and concentrated. The crude compound 23 was used for the nextreaction without further purification.

Synthesis of Compound 24

A mixture of KO^(t)Bu (0.487 g, 4.12 mmol) and MePPh₃Br (1.47 g, 4.12mmol) in THF (6 mL) was stirred at ambient temperature for 1 hour underargon then compound 23 (0.773 g, 1.37 mmol) in THF (6 mL) was added. Thereaction mixture was stirred at ambient temperature overnight then wasdiluted with EtOAc (40 mL) and washed with brine (2×30 mL) then wasdried over MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 1:1) to afford compound 24(0.606 g, 79%) as a white solid.

Synthesis of Compound 25

A solution of compound 24 (0.15 g, 0.267 mmol) and Bu₄NF (0.4 mL of a1.0 M solution in THF) in THF (5 mL) was refluxed under argon for 2hours. The solvent was evaporated under reduced pressure and the residuewas purified by chromatography on silica gel (MeOH/EtOAc, 2:98) to givecompound 25 (0.073 g, 82%) as a white solid: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 287.10; C₂₀H₃₁O.

Example 2

Compound 29, a representative compound of the invention, may be preparedaccording to the following Reaction Scheme 2. Any number of compoundsrelated to compound 29 could be produced using similar methodology.Starting compound 20 may be prepared according to procedures set forthin Example 1 above.

In general, treatment of lactone compound 20 with MeLi in THF gives thelactol compound 26. Baeyer-Villager oxidation using MCPBA in CHCl₃ givescompound 27. Treatment with 80% acetic acid removes the ketal and theTBS group to give compound 28. Reaction of compound 28 withmethyltriphenyl-phosphonium bromide and KO^(t)Bu in THF introduces themethylidene group and removes the acyl group to give compound 29.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 26

To a 0° C. solution of compound 20 (2.0 g, 4.18 mmol) in dry THF (12 mL)was added dropwise MeLi (8.95 mL of a 1.4 M solution in ether). Thereaction mixture was stirred for 2 hours then was poured over ice andextracted with EtOAc (3×100 mL). The combined organic layer was washedwith brine (2×50 mL) then was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(hexane/EtOAc, 8:2) to yield compound 26 (1.49 g, 72%) as a white solid.

Synthesis of Compound 27

To a solution of compound 26 (1.49 g, 3.00 mmol) in chloroform was addedMCPBA (1.8 g, 6.00 mmol). The reaction mixture was stirred at ambienttemperature for 20 hours then was diluted with EtOAc (200 mL). Thesolution was washed successively with 5% NaHSO₃ solution (2×100 mL),saturated K₂CO₃ solution (2×50 mL) and brine (2×50 mL) then was driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (hexane/EtOAc, 9:1) to afford compound 27(1.3 g, 85%) as a white solid.

Synthesis of Compound 28

A mixture of compound 27 (400 mg, 0.783 mmol) and 80% acetic acid (5 mL)was stirred at 50° C. for 5 hours then was diluted with toluene (50 mL)and concentrated. The residue was purified by chromatography on silicagel (hexanes/acetone, 1:1) to yield compound 28 (322 mg, 86%) as a whitesolid.

Synthesis of Compound 29

A mixture of KO^(t)Bu (286 mg, 2.55 mmol) and MePPh₃Br (911 mg, 2.55mmol) in THF (2 mL) was stirred at ambient temperature for 1 hour underargon, then compound 28 (300 mg, 0.85 mmol) in THF (2 mL) was added. Thereaction mixture was refluxed for 4 hours then was cooled to ambienttemperature and diluted with water (5 mL). The solution was extractedwith EtOAc (3×50 mL) and washed with brine (2×20 mL) then was dried overNa₂SO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 2:8) to afford compound 29(144 mg, 55%) as a white solid: LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 273.01; C₁₉H₂₉O.

Example 3

Compound 38, a representative compound of the invention, may be preparedaccording to the following Reaction Scheme 3. Any number of compoundsrelated to compound 38 could be produced using similar methodology.Starting compound 30 may be prepared according to the proceduresoutlined in U.S. Pat. No. 6,046,185.

In general, dihydroxylation of compound 30 using osmium tetraoxide inpyridine gives compound 31. Oxidative cleavage of the diol using leadtetraacetate in CH₂Cl₂ gives compound 32. Selective reduction of thealdehyde group using LiBEt₃H in THF gives compound 33. Reaction ofcompound 33 with TBDPSCl and imidazole in DMF protected the freehydroxyl to give compound 34. Lithium aluminum hydride reduction of theketone group gives compound 35. Treatment with 80% acetic acid removesthe ketal to give compound 36. Olefination usingmethyltriphenylphosphonium bromide and KO^(t)Bu in THF gives themethylidene compound 37. Treatment with a refluxing solution of Bu₄NF inTHF removes the TBDPS group to give compound 38.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 31

To a solution of compound 30 (0.45 g, 0.89 mmol) in pyridine (2.5 mL)was added OsO₄ (0.25 g, 0.98 mmol). The reaction mixture was stirred at90° C. overnight then a solution of Na₂S₂O₃ (0.5 g) in a mixture ofwater (8 mL) and pyridine was added. The reaction mixture was stirredfor 20 minutes then extracted with CH₂Cl₂ (2×20 mL) and washed withbrine (30 mL), then dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc,4:1) to afford compound 31 (0.249 g, 58%) as a white solid.

Synthesis of Compound 32

To a solution of compound 31 (0.52 g, 1.08 mmol) in CH₂Cl₂ was addedPb(OAc)₄ (0.527 g, 1.19 mmol). The reaction mixture was stirred atambient temperature for 10 minutes under argon. A precipitate wasremoved by filtration and the solvent was evaporated under reducedpressure. The residue was filtered through a silica gel plug(hexanes/EtOAc, 1:1) to afford compound 32 (0.482 g, 58%) as a whitesolid.

Synthesis of Compound 33

To a solution of compound 32 (0.562 g, 1.17 mmol) in THF at 0° C. wasadded LiBEt₃H (1.29 mL of a 1M solution in THF). The reaction mixturewas stirred at ambient temperature for 40 minutes under argon then wascooled in an ice bath and NaOH (1.29 mL, 1 M) and H₂O₂ (0.2 mL, 30%)were slowly added. The resulting solution was stirred at 0° C. for anadditional 5 minutes. The solution was extracted with CH₂Cl₂ (2×15 mL)and the extracts were dried over MgSO₄, filtered concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc,75:25 to 40:60) to afford compound 33 (256 mg, 46%) as a white solid.

Synthesis of Compound 34

A solution of compound 33 (0.185 g, 0.385 mmol), TBDPSCl (0.175 mL,0.673 mmol) and imidazole (0.09 g, 1.161 mmol) in dry DMF (4 mL) wasstirred overnight. The reaction mixture was diluted with toluene (30 mL)and washed with brine (2×15 mL) then was dried over MgSO₄, filtered andconcentrated. The crude compound 34 was used for the next reactionwithout further purification.

Synthesis of Compound 35

To a solution of compound 34 (crude, 0.104 mmol) in THF at 0° C. wasadded LiAlH₄ (0.1 mL of a 1 M solution in THF) under argon. The reactionmixture was stirred at 0° C. for 1 hour, then brine (5 mL) was slowlyadded. The solution was extracted with CH₂Cl₂ (2×15 mL) and the extractswere dried over MgSO₄, filtered concentrated. The residue was purifiedby chromatography on silica gel (hexanes/EtOAc, 2:3) to afford compound35 (39 mg, 51% over two steps) as a white solid.

Synthesis of Compound 36

A mixture of compound 35 (120 mg, 0.197 mmol) and 80% acetic acid (1.5mL) was stirred at ambient temperature overnight then was diluted withtoluene (10 mL) and concentrated. The crude compound 36 was used for thenext reaction without further purification.

Synthesis of Compound 37

A mixture of KO^(t)Bu (60 mg, 0.54 mmol) and MePPh₃Br (194 mg, 0.54mmol) in THF (0.9 mL) was stirred at ambient temperature for 1 hourunder argon then compound 36 (97 mg, 0.17 mmol) was added. The reactionmixture was stirred at ambient temperature for 3 hours then was dilutedwith EtOAc (80 mL) and washed with brine (2×30 mL) then was dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 2:3) to afford compound 37(63 mg, 65%) as a white solid.

Synthesis of Compound 38

A solution of compound 37 (59 mg, 0.105 mmol) and n-Bu₄NF (0.16 mL of a1.0 M solution in THF) in THF (0.35 mL) was refluxed under argon for 2hours. The solvent was evaporated under reduced pressure and the residuewas purified by chromatography on silica gel (MeOH/EtOAc, 2:98) toafford compound 38 (38 mg) as a white solid: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 286.93; C₂₀H₃₁O.

Example 4

Compound 45, a representative compound of the invention, may be preparedaccording to the following Reaction Scheme 4. Any number of compoundsrelated to compound 45 could be produced using similar methodology.Starting compound 18 may be prepared according to procedures outlined inU.S. Pat. No. 6,046,185.

In general, oxidative ring opening of compound 18 using sodium periodateand a catalytic amount of ruthenium oxide gives compound 39. Reactionwith lithium aluminum hydride in THF gives compound 40. Oxidativecleavage of the diol using lead tetraacetate in CH₂Cl₂ gives lactonecompound 41. Treatment with MeLi in THF gives the lactol compound 42.Baeyer-Villager oxidation using MCPBA in CHCl₃ gives compound 43.Treatment with 80% acetic acid removes the ketal and TBS group to givecompound 44. Reaction of compound 44 with methyltriphenylphosphoniumbromide and KO^(t)Bu in THF introduces the methylidene group andsubsequent treatment with K₂CO₃ in refluxing methanol removes the acylgroup to give compound 45.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 39

To a solution of NaIO₄ (13.96 g, 65.2 mmol) and RuO₂.H₂O (87 mg, 0.66mmol) in water (120 mL) were added CCl₄ (80 mL) and acetone (100 mL).Compound 18 (crude, 0.81 mmol), in a mixture of CCl₄ (40 mL) and acetone(60 mL) was then slowly added. The reaction mixture was stirred atambient temperature for 3 hours. The solution was extracted with CH₂Cl₂(2×200 mL) and the combined organic layer was washed with brine (200 mL)then was dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel (hexanes/EtOAc/MeOH, 70:25:5)to afford compound 39 (3.41 g, 37%) as a white solid.

Synthesis of Compound 40

To a solution of compound 39 (0.509 g, 1.00 mmol) in THF was slowlyadded LiAlH₄ (3 mL of a 1 M solution in THF). The reaction mixture wasstirred for 2 hours then saturated NaHCO₃ (5 mL) was slowly added. Thesolution was extracted with CH₂Cl₂ (2×20 mL) and the extracts were driedover MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (MeOH/EtOAc, 5:95) to afford compound 40(0.16 g, 32%) as a white glassy solid.

Synthesis of Compound 41

To a solution of compound 40 (0.16 g, 0.32 mmol) in CH₂Cl₂ was addedPb(OAc)₄ (0.156 g, 0.35 mmol). The reaction mixture was stirred atambient temperature for 10 minutes under argon. A precipitate wasremoved by filtration and solvent was evaporated under reduced pressure.The residue was purified by chromatography on silica gel (hexanes/EtOAc,9:1) to afford compound 41 (0.113 g, 87%) as a white glassy solid.

Synthesis of Compound 42

To a solution of compound 41 (0.20 g, 0.43 mmol) in THF (3 mL) at 0° C.was added MeLi (1.5 mL of a 1.4 M solution in diethyl ether) underargon. The reaction mixture was stirred at ambient temperature for 2hours then was quenched with saturated NH₄Cl (15 mL) and extracted withEtOAc (2×15 mL) then was dried over MgSO₄, filtered and concentrated.The crude compound 42 was used for the next reaction without furtherpurification.

Synthesis of Compound 43

A mixture of compound 42 (crude, 0.43 mmol) and MCPBA (0.26 g, 57-86%,1.51 mmol) in chloroform (3 mL) was stirred at ambient temperature for 1day. The reaction mixture was diluted with EtOAc (15 mL) and washedsuccessively with saturated Na₂SO₃ (20 mL), saturated NaHCO₃ (20 mL) andbrine (20 mL), then was dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc,4:1) to afford compound 43 (66 mg, 31% over two steps) as a white solid.

Synthesis of Compound 44

A mixture of compound 43 (0.40 g, 0.81 mmol) and 80% acetic acid (5 mL)was stirred at 50° C. for 2 hours, then was diluted with toluene (20 mL)and concentrated. The crude compound 44 was used for the next reactionwithout further purification.

Synthesis of Compound 45

A mixture of KO^(t)Bu (0.45 g, 4.05 mmol) and MePPh₃Br (1.45 g, 4.05mmol) in THF (10 mL) was stirred at ambient temperature for 1 hour underargon then compound 44 (crude, 0.81 mmol) in THF (5 mL) was added. Thereaction mixture was stirred at ambient temperature overnight then wasdiluted with CH₂Cl₂ (50 mL) and washed with brine (2×30 mL), then driedover MgSO₄, filtered and concentrated. The crude product was refluxedwith K₂CO₃ (0.34 g, 2.42 mmol) in THF (5 mL) for 3 hours. The solventwas removed and the residue was purified by chromatography on silica gel(hexane/EtOAc/MeOH, 5:5:0.5) to afford compound 45 (0.13 g, 55% over twosteps) as a white solid: LC/MS (direct infusion, electrospray +ve, 10 mMNH₄OAc in 3:7 water and MeCN) 317.00; C₁₈H₃₀NaO₃.

Example 5

Compound 51, a representative compound of the invention, may be preparedaccording to the following Reaction Scheme 5. Starting compound 46 maybe prepared according to the procedures outlined in U.S. Pat. No.6,046,185. Any number of compounds related to compound 51 could beproduced using similar methodology.

In general, reaction of compound 46 with sodium periodate in THFoxidatively cleaves the diol to give compound 47. Sodium borohydridereduction of the aldehyde groups gives compound 48. Treatment with 80%acetic acid removes the ketal and TBS group to give compound 49.Reaction with TBSCl and imidazole in DMF protected the hydroxyls to givecompound 1. Olefination using methyltriphenylphosphonium bromide andKO^(t)Bu in THF gives compound 50. Treatment with 80% acetic acidfollowed by a refluxing solution of Bu₄NF in THF removes the TBS groupsto give compound 51.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 47

A solution of compound 46 (450 mg, 0.94 mmol), NaIO₄ (240 mg, 1.12mmol), water (2 mL) and THF (4 mL) was stirred overnight at ambienttemperature. The reaction mixture was diluted with EtOAc and washed withbrine then was dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography on silica gel (EtOAc/hexanes,15:85) to afford compound 47 (140 mg, 31%) as a white solid.

Synthesis of Compound 48

A solution of compound 47 (1.32 g, 2.76 mmol), NaBH₄ (229 mg, 6.06mmol), MeOH (17 mL) and CH₂Cl₂ (3 mL) was stirred at 0° C. for 4 hours,then at ambient temperature overnight. The solvents were evaporatedunder reduced pressure and the residue was diluted with EtOAc and washedwith brine. The EtOAc layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (EtOAc/hexanes, 2:3) to afford compound 48 (0.35 g, 26%) as awhite solid.

Synthesis of Compound 49

A mixture of compound 48 (350 mg, 0.72 mmol) and 80% acetic acid (20 mL)was stirred overnight at ambient temperature. The solvents wereevaporated under reduced pressure and the residual solvent was removedby co-distillation with toluene to afford compound 49 (250 mg, 100%) asa yellow solid.

Synthesis of Compound 1

A solution of compound 49 (impure, 0.72 mmol), TBSCl (382 mg, 2.54mmol), imidazole (346 mg, 5.08 mmol) in dry DMF (15 mL) was stirred atambient temperature overnight. The reaction mixture was diluted withEtOAc (100 mL), washed with water, then was dried over Na₂SO₄, filteredand concentrated. The residue was purified by chromatography on silicagel (EtOAc/hexanes, 5:95) to afford compound 1 (374 mg, 78%).

Synthesis of Compound 50

A mixture of KO^(t)Bu (191 mg, 1.7 mmol) and MePPh₃Br (600 mg, 1.7 mmol)in THF (1.5 mL) was stirred at ambient temperature for 1 hour underargon, then compound 1 (374 mg, 0.56 mmol) in THF (1.5 mL) was added.The reaction mixture was heated at reflux for 3 hours then was dilutedwith water (3 mL) and extracted with EtOAc (30 mL). The EtOAc layer waswashed with water (10 mL) and brine (10 mL) then was dried over Na₂SO₄,filtered and concentrated. The residue was eluted through silica gel(EtOAc/hexanes, 1:99) to afford compound 50 (354 mg, 95%) as a yellowoil.

Synthesis of Compound 51

A mixture of compound 50 (350 mg, 0.53 mmol) and 80% acetic acid (10 mL)was heated at 50° C. for 6 hours. The solvents were evaporated underreduced pressure and residual solvent was removed by co-distillationwith toluene. The residue still contained some TBS protected material,therefore the residue was taken up in THF (1 mL) and Bu₄NF (2.5 mL of a1.0 M solution in THF) and the resulting solution was heated at refluxfor 3.5 hours. The reaction mixture was diluted with EtOAc and washedwith water and brine then was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (EtOAc) to afford compound 51 (119 mg, 70%) as a pale yellowsolid: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7water and MeCN) 305.16; C₂₀H₃₂O₂, 287.19; C₂₀H₃₀O.

Example 6

Compound 59, a representative compound of the invention may be preparedaccording to the following Reaction Scheme 6. Any number of compoundsrelated to compound 59 could be produced using similar methodology.Starting compound 27 may be prepared according to procedures describedabove in Example 2.

In general, reaction of compound 27 with acetic anhydride and DMAP inpyridine gives compound 52. Treatment with 80% acetic acid removes theketal and the TBS group to give compound 53. Reaction withmethyltriphenylphosphonium bromide and KO^(t)Bu in toluene introducesthe methylidene group and removes the acyl group from the primaryhydroxyl to give compound 54. Treatment with TBSCl, DMAP and Et₃N in DMFselectively protects the primary hydroxyl to give compound 55. The freehydroxyl in compound 55 is converted to the bromide compound 56 usingbromine, triphenylphosphine and Et₃N in THF. Azide displacement of thebromine using sodium azide in NMP gives compound 57. Reaction withlithium aluminum hydride in THF reduces the azide and removes the acylgroup to give compound 58. Treatment with 80% acetic acid removes theTBS group and forms the ammonium acetate salt to give compound 59.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 52

A solution of compound 27 (3.08 g, 5.87 mmol), acetic anhydride (1.12mL, 11.7 mmol) and DMAP (50 mg, 0.41 mmol) in pyridine (25 mL) wasstirred overnight. The reaction mixture was then quenched with brine (80mL) and extracted with EtOAc (200 mL). The EtOAc layer was washed withbrine (2×60 mL), then dried (MgSO₄), filtered and concentrated. Thecrude compound 52 was used directly in the next step.

Synthesis of Compound 53

A mixture of compound 52 (crude, 5.87 mmol) and 80% acetic acid (40 mL)was stirred at 50° C. for 1 hour, then co-distilled with toluene (3×50mL) and concentrated. The crude compound 53 was used directly in thenext step.

Synthesis of Compound 54

A mixture of KO^(t)Bu (2.02 g, 18.0 mmol) and MePPh₃Br (6.43 g, 18.0mmol) in toluene (45 mL) was stirred at ambient temperature for 1 hourunder argon, then compound 53 (crude, 5.87 mmol) in toluene (10 mL) wasadded. The reaction mixture was stirred at ambient temperatureovernight, then diluted with saturated NH₄Cl solution (100 mL) andextracted with EtOAc (100 mL). The EtOAc layer was washed with brine (80mL), then dried (MgSO₄), filtered and concentrated. The residue waseluted through silica gel (hexanes/acetone, 7:3) to afford impurecompound 54.

Synthesis of Compound 55

A solution of compound 54 (impure, 2.85 mmol), TBSCl (490 mg, 3.25mmol), DMAP (58 mg, 0.47 mmol) and Et₃N (600 μl, 4.3 mmol) in dry DMF (6mL) was stirred for 5 hours. The reaction mixture was diluted withtoluene (80 mL), washed with saturated NaHCO₃ solution and brine, thendried (MgSO₄), filtered and concentrated. The residue was purified bychromatography on silica gel to afford compound 55 (480 mg, 45%).

Synthesis of Compound 56

Bromine (80 μL, 1.6 mmol) was added to a solution of Ph₃P (407 mg, 1.6mmol) in THF (5 mL) at ambient temperature. After 5 minutes Et₃N (290 L,2.1 mmol) was added followed by a solution of compound 55 (480 mg, 1.03mmol) in THF (5 mL). After 1.5 hours the reaction mixture was dilutedwith EtOAc (100 mL) and washed with water and brine, then dried overMgSO₄, filtered and concentrated. The residue was purified by columnchromatography (hexanes/EtOAc, 95:5) to afford compound 56 (510 mg,94%).

Synthesis of Compound 57

A solution of compound 56 (510 mg, 0.97 mmol), NaN₃ (200 mg, 3.1 mmol)and NMP (8 mL) was heated at 55° C. for 4 hours. The reaction mixturewas diluted with toluene (100 mL) and EtOAc (30 mL) and washed withwater and brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by column chromatography (hexanes/EtOAc, 98:2) toafford compound 57 (197 mg, 41%).

Synthesis of Compound 58

To a solution of compound 57 (197 mg, 0.40 mmol) in THF at ambienttemperature was added LiAlH₄ (1 mL of a 1.0 M solution in ether). Thereaction mixture was stirred at ambient temperature for 2.5 hours thenNa₂SO₄.10H₂O was added. The solution was filtered and the solid waswashed with MeOH and CH₂Cl₂. The filtrate was concentrated and theresidue was purified by chromatography on silica gel (CHCl₃/MeOH/Et₃N,90:8:2) to afford compound 58 (144 mg, 78%).

Synthesis of Compound 59

A mixture of compound 58 (114 mg, 0.27 mmol) and 80% acetic acid (7 mL)was stirred overnight at ambient temperature. The solution was dilutedwith toluene (3×50 mL) and concentrated to afford compound 59 (58 mg,59%) as a yellow solid: LC/MS (direct infusion, electrospray +ve, 10 mMNH₄OAc in 3:7 water and MeCN) 307.92; C₁₉H₃₄NO₂.

Example 7

Compounds 67 and 68, representative compounds of the invention, may beprepared according to the following Reaction Scheme 7. Any number ofcompounds related to compounds 67 and 68 could be produced using similarmethodology. Starting compound 21 may be prepared according toprocedures described above in Example 1.

In general, treatment of compound 21 with acetic anhydride in pyridine(to protects the free hydroxyls) gives compound 60. Treatment with 80%acetic acid removes the ketal and the TBS groups to give compound 61.Treatment with TBSCl and imidazole in DMF protects the free hydroxyl incompound 62. Olefination of compound 62 with methyltriphenylphosphoniumbromide and KO^(t)Bu in toluene introduces the methylidene group. Insome instances the olefination conditions result in removal of theacetate from the primary hydroxyl giving a compound such as 63. Theprimary acetate may be selectively hydrolyzed by reaction with K₂CO₃ inrefluxing methanol. The free hydroxyl in compound 63 is converted to themesylate compound 64 using MsCl and pyridine. Azidation using sodiumazide in DMF gives the azido compound 65. Lithium aluminum hydridereduction of the azide in THF gives the amine compound 66. Treatmentwith 80% acetic acid removes the TBS group and forms the ammoniumacetate salt to give compound 67.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 60

To a solution of compound 21 (0.686 g, 1.42 mmol) in pyridine (5 mL) wasadded acetic anhydride (0.94 mL, 9.94 mmol) and the reaction mixture wasstirred at 50° C. overnight. The solution was diluted with EtOAc (25 mL)and washed with brine (2×20 mL), then dried over MgSO₄, filtered andconcentrated. The crude compound 60 was used for the next reactionwithout further purification.

Synthesis of Compound 61

A mixture of compound 60 (crude, 1.42 mmol) and 80% acetic acid (15 mL)was stirred at 50° C. for 2 hours, then diluted with toluene (2×20 mL)and concentrated. The residue was purified by chromatography on silicagel (hexanes/EtOAc, 1:2) to afford compound 61 (0.479 g, 87%) as a whitesolid.

Synthesis of Compound 62

A solution of compound 61 (0.971 g, 2.38 mmol), TBSCl (0.716 g, 4.75mmol) and imidazole (0.647 g, 9.51 mmol) in dry DMF (10 mL) was stirredfor 3 hours. The reaction mixture was diluted with toluene (50 mL) andwashed with brine (2×20 mL), then dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc, 4:1) to afford compound 62 (1.218 g, 98%) as a viscouspale yellow oil.

Synthesis of Compound 63

A mixture of KO^(t)Bu (5.00 g, 42.3 mmol) and MePPh₃Br (15.1 g, 42.3mmol) in toluene (100 mL) was stirred at ambient temperature for 1 hourunder argon, then a solution of compound 62 (crude, 14.1 mmol) in 100 mLof toluene was added. The reaction mixture was stirred overnight atambient temperature, then quenched with saturated NaHCO₃ solution (75mL) and water (75 mL). The solution was further diluted with 100 mL ofwater and was extracted with EtOAc (4×100 mL).

The combined extracts solution was washed with brine (2×100 mL), thendried over MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 100:0, then 9:1, then 4:1)to afford the diacetate compound (4.5 g, 62%) as a yellow oil andcompound 63 (1.8 g, 27%) as a yellow oil. A solution of the diacetatecompound (4.5 g, 8.6 mmol), K₂CO₃ (4.78 g, 34.6 mmol) and methanol (100mL) was heated at reflux under argon. After 75 minutes the reactionmixture was cooled to ambient temperature and filtered through celiteeluting with CH₂Cl₂. The filtrate was concentrated and dissolved inEtOAc (250 mL), then washed with water and dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography on silicagel (hexanes/EtOAc, 100:0, then 19:1, then 9:1) to afford compound 63(3.2 g, 47%) as a yellow foam.

Synthesis of Compound 64

To a solution of compound 63 (3.17 g, 6.62 mmol) in pyridine (50 mL) andCH₂Cl₂ (0.5 mL) was added methanesulfonyl chloride (1.02 mL, 13.2 mmol)and the reaction mixture was stirred under argon at ambient temperaturefor 3 hours. The reaction was quenched with saturated NaHCO₃ solution(60 mL) and extracted with EtOAc (3×80 mL). The combined extractssolution was washed with water and brine, then dried over MgSO₄,filtered and concentrated. The residue was concentrated from toluene toafford crude compound 64 that was used for the next reaction withoutfurther purification.

Synthesis of Compound 65

A solution of compound 64 (crude, 6.62 mmol) and NaN₃ (646 mg, 9.93mmol) in DMF (40 mL) was heated under argon at 60° C. overnight. Aftercooling, the reaction mixture was diluted with water (100 mL) and wasextracted with diethyl ether (4×100 mL). The combined extracts solutionwas washed with water and brine, then dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc, 100:0, then 98:2, then 95:5) to afford compound 65 (2.56g, 77% for 2 steps) as a yellow oil.

Synthesis of Compound 66

A solution of LiAlH₄ (3.85 mL of a 1.0 M solution in THF) was added to asolution of compound 65 (647 mg, 1.28 mmol) in THF (15 mL) under argon.After 3 hours the reaction mixture was quenched with Na₂SO₄.10H₂O anddiluted with THF (10 mL). After 30 minutes the solution was filtered andconcentrated. The residue was purified by chromatography on silica gel(CH₂Cl₂/MeOH/Et₃N, 100:0:0, then 95:5:0, then 90:10:0, then 95:5:2) toafford compound 66 (324 mg, 58%) as a colourless oil.

Synthesis of Compound 67

A solution of compound 66 (320 mg, 0.734 mmol) and 80% acetic acid (25mL) was heated at 50° C. for 3 hours. The residue was purified bychromatography on reverse-phase silica gel (H₂O, then H₂O/MeOH/AcOH50:50:2). Concentration from MeOH/MeCN gave compound 67 (244 mg, 87%) asa white solid: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 322.12; C₂₀H₃₆NO₂.

Synthesis of Compound 68

Using the procedures described for the synthesis of compound 67, withthe exception of olefination by EtPPh₃Br, compound 68 (75 mg) wasprepared as a white solid in 22% yield starting from compound 62. LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)336.16; C₂₁H₃₈NO₂.

Example 8

Compounds 77-81, representative compounds of the invention, may beprepared according to the following Reaction Scheme 8. Startingcompounds such as 69 may be prepared according to the proceduresoutlined in U.S. Pat. No. 6,046,185.

Any number of compounds related to compounds 77-81 could be producedusing similar methodology.

In general, reaction of compound 69 with acetic anhydride and DMAP inpyridine gives compound 70. Treatment with 80% acetic acid removes theacetonide group to give compound 71. Reaction with sodium periodate inTHF oxidatively cleaves the diol to give compound 72. Sodium borohydridereduction of the aldehyde groups gives compound 73. Reaction with aceticanhydride and DMAP in pyridine selectively protects the one primaryhydroxyl to give compound 74. The free hydroxyl is converted to themesylate compound 75 using MsCl and pyridine. Reaction with sodium azidein DMF gives the azido compound 76. Reaction with lithium aluminumhydride in THF reduces the azide and removes the acyl groups to givecompound 77. Treatment with 80% acetic acid forms compound 78 as theammonium acetate salt. Reaction of a compound such as 78 with HCl inwater and MeOH facilitates migration of the 18-methyl group to C17 togive a compound such as 79. Careful treatment of compound 77 with HCl inMeCN and water forms the ammonium chloride salt of compound 77 (i.e.,compound 80).

Following are specific examples of the compounds prepared above.

Synthesis of Compound 70

A solution of compound 69 (6.9 g, 19.1 mmol), acetic anhydride (3.62 mL,38.3 mmol) and DMAP (0.23 g, 1.9 mmol) in pyridine (50 mL) was stirredfor 4.5 hours.

The reaction mixture was diluted cold water (150 mL) and extracted withEtOAc (600 mL) and washed with brine (2×200 mL), then dried over MgSO₄,filtered and concentrated. The crude compound 70 was used directly inthe next step.

Synthesis of Compound 71

A mixture of compound 70 (crude, 19.1 mmol) and 80% acetic acid (50 mL)was stirred at 40° C. for 2 hours. The solution was concentrated toafford crude compound 71 that was used in the next step without furtherpurification.

Synthesis of Compound 72

A solution of compound 71 (crude, 19.1 mmol), NaIO₄ (8.19 g, 38.3 mmol),water (53 mL) and THF (106 mL) was stirred at ambient temperature for3.5 hours. The reaction mixture was diluted with CH₂Cl₂ and was washedwith brine, then dried over MgSO₄, filtered and concentrated to affordcrude compound 72 that was used in the next step without furtherpurification.

Synthesis of Compound 73

A solution of compound 72 (crude, 19.1 mmol), NaBH₄ (1.45 g, 38.3 mmol),THF (120 mL) and MeOH (40 mL) was stirred at 0° C. for 10 minutes, thenat ambient temperature for 1 hour. The mixture was cooled in ice and 80%acetic acid (62 mL) was slowly added. The solution was stirred atambient temperature for 10 minutes, then diluted with EtOAc (400 mL) andthen washed with brine. The EtOAc layer was dried over MgSO₄, filteredand concentrated to afford crude compound 73 which was used in the nextstep without further purification.

Synthesis of Compound 74

A solution of compound 73 (crude, 19.1 mmol), acetic anhydride (2.1 mL,22.0 mmol) and DMAP (230 mg, 1.9 mmol) in pyridine (65 mL) was stirredat ambient temperature for 1.5 hours. The reaction mixture was dilutedwith EtOAc (400 mL) and washed with brine, then dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel (hexanes/EtOAc, 5:1 then 4:1 then 7:3) to afford compound 74(4.9 g, 63%).

Synthesis of Compound 75

To a solution of compound 74 (4.9 g, 12.1 mmol) in pyridine (40 mL) wasadded methanesulfonyl chloride (1.68 mL, 21.7 mmol) and the reactionmixture was stirred at ambient temperature for 2 hours. The solution wasdiluted with EtOAc (400 mL) and washed with brine, then dried overMgSO₄, filtered and concentrated to afford crude compound 75 that wasused for the next reaction without further purification.

Synthesis of Compound 76

A mixture of compound 75 (crude, 12.1 mmol) and NaN₃ (1.57 g, 24.1 mmol)in DMF (100 mL) was heated under argon at 60° C. overnight. Aftercooling, the reaction mixture was diluted with toluene (400 mL) and waswashed with brine, then dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc,8:2) to afford compound 76 (4.8 g, 92% for 2 steps).

Synthesis of Compound 77

A solution of LiAlH₄ (44.5 mL of a 1.0 M solution in Et₂O) was added toan ice cooled solution of compound 76 (4.8 g, 11.1 mmol) in THF (111mL). After 10 minutes the solution was continued at ambient temperaturefor another 4 hours. The reaction mixture was cooled in ice and quenchedwith Na₂SO₄.10H₂O. After 15 minutes the solution was diluted with EtOAc(100 mL), stirred for an additional 20 minutes at ambient temperature,then filtered. The filtrate was washed with brine, then dried overMgSO₄, filtered and concentrated to afford compound 77 (3.8 g,quantitative) as a white solid.

Synthesis of Compound 78

A solution of compound 77 (1.00 g, 2.93 mmol) and 80% acetic acid (15mL) was heated at 40° C. for 1 hour, then concentrated. Residual solventwas removed by codistillation with toluene. The residue was trituratedin diethyl ether and filtered to give compound 78 (923 mg, 83%) as awhite solid. LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 321.95; C₂₀H₃₆NO₂.

Synthesis of Compound 79

A solution of compound 78 (600 mg, 1.57 mmol), concentrated HCl (5drops), water (1 mL) and MeOH (9 mL) was heated at 65° C. for 5 days,then concentrated. The residue was triturated in MeCN and filtered togive compound 79 (504 mg, 90%) as a white solid. LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 322.2; C₂₀H₃₆NO₂.

Synthesis of Compound 80

To a suspension of compound 77 (0.1 g, 0.3 mmol) in MeCN (2 mL) wasadded HCl (337 L of a 1.0 M solution in Et₂O). After 15 minutes thesolution was filtered to afford the ammonium chloride salt of compound77, i.e., compound 80 (76 mg, 72%) as a white powder.

Synthesis of Compound 81

Using the procedures described for the synthesis of compound 80,compound 81 (0.646 g) was prepared as a white powder in 37% yieldstarting from the ethylidene compound analogous to compound 69. The saltformation step differed in that the compound was isolated bycodistillation of the residual acid solution using MeOH: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 335.89;C₂₁H₃₈NO₂.

Example 9

Compounds 88 and 89, representative compounds of the invention, may beprepared according to the following Reaction Scheme 9. Any number ofcompounds related to compounds 88-89 could be produced using similarmethodology. Starting compound 73 may be prepared according to theprocedures described above in Example 8.

In general, reaction of compound 73 with TBSCl and imidazole in DMFgives compound 83. Reaction with acetic anhydride and DMAP in pyridineprotects the remaining free hydroxyl to give compound 84. Reaction withtetrabutylammonium fluoride removes the TBS group to give compound 85.The free hydroxyl is converted to the mesylate compound 86 using MsCland pyridine. Reaction with sodium azide in DMF gives the azido compound87. Reaction with lithium aluminum hydride in THF reduces the azide andremoves the acyl groups to give compound 88. Treatment with 80% aceticacid forms the ammonium acetate salt to give compound 89.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 83

A solution of compound 73 (2.9 g, 7.92 mmol), TBSCl (1.32 g, 8.76 mmol),imidazole (813 mg, 11.9 mmol) and DMF (20 mL) was stirred at ambienttemperature for 1.5 hours. The solution was diluted with water (50 mL)and was extracted with toluene (100 mL). The toluene layer was washedwith brine (40 mL), then dried over MgSO₄, filtered and concentrated togive crude compound 83 that was used in the next step without furtherpurification.

Synthesis of Compound 84

A solution of compound 83 (crude, 7.96 mmol), acetic anhydride (2.25 mL,23.9 mmol) and DMAP (100 mg, 0.82 mmol) in pyridine (25 mL) was stirredat ambient temperature for 1 hour. The reaction mixture was diluted withEtOAc and washed with brine, then dried over MgSO₄, filtered andconcentrated. The crude compound 84 was used in the next step withoutfurther purification.

Synthesis of Compound 85

A solution of compound 84 (crude g, 7.96 mmol), Bu₄NF (12 mL of a 1.0 Msolution in THF) and THF was stirred at ambient temperature for 2 hoursand at 40° C. for 30 minutes. The reaction mixture was filtered throughsilica gel and concentrated.

The residue was purified by chromatography on silica gel (EtOAc/hexanes3:7) to afford compound 85 (2.06 g, 64%).

Synthesis of Compound 86

To a solution of compound 85 (1.06 g, 2.61 mmol) in pyridine (12 mL) wasadded methanesulfonyl chloride (400 L, 5.16 mmol) and the reactionmixture was stirred at ambient temperature for 2 hours. The reaction wasquenched with water and was extracted with EtOAc. The solution washedwith brine, then dried over MgSO₄, filtered and concentrated to affordcrude compound 86 which was used for the next reaction without furtherpurification.

Synthesis of Compound 87

A mixture of compound 86 (crude, 2.61 mmol) and NaN₃ (1.0 g, 15 mmol) inDMF (15 mL) was heated under argon at 95° C. overnight. After cooling,the reaction mixture was diluted with toluene and was washed with brine,then dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel to afford compound 87 (575 mg,89%).

Synthesis of Compound 88

A solution of LiAlH₄ (3.2 mL of a 1.0 M solution in THF) was added to anice cooled solution of compound 87 (274 mg, 0.635 mmol) in THF (3 mL).After 10 minutes the solution was continued at ambient temperature foranother 3 hours. The reaction mixture was cooled in ice and quenchedwith Na₂SO₄.10H₂O. After 15 minutes the solution was filtered and thefiltrate was washed with brine, then dried over MgSO₄, filtered andconcentrated. Purification by chromatography on silica gel(EtOAc/MeOH/H₂O/NH₄OH 7:2:1:0.15, then 7:2:1:0.2, then 7:2:1:0.3)afforded compound 88 (135 mg, 66%).

Synthesis of Compound 89

A solution of compound 88 (135 mg, 0.42 mmol) and 80% acetic acid (3 mL)was heated at 40° C. for 30 minutes, then concentrated. Residual solventwas removed by codistillation with methanol to give compound 89 (158 mg,99%) as a pale yellow foam. LC/MS (direct infusion, electrospray +ve, 10mM NH₄OAc in 3:7 water and MeCN) 322.11; C₂₀H₃₆NO₂.

Example 10

Compounds 100 and 101, a representative compound of the invention, maybe prepared according to the following Reaction Scheme 10. Any number ofcompounds related to compounds 100 and 101 could be produced usingsimilar methodology. Starting compound 60 may be prepared according toprocedures described above in Example 7.

In general, selective hydrolysis of the primary acetate in compound 60using K₂CO₃ gives compound 90. The free hydroxyl is reacted to give themesylate compound 91 using MsCl and pyridine. Mesylate displacement byphenylselenide gives compound 92. Oxidative elimination using hydrogenperoxide gives the olefin compound 93. Osmolation gives dihydroxylatedcompound 94, which is then oxidatively cleaved by lead tetraacetate togive compound 95. Sodium borohydride reduction gives alcohol compound96. Azidation using diisopropyl azodicarboxylate (DIAD),diphenylphosphoryl azide (DPPA) and PPh₃ in THF gives the azido compound97.

Reaction with lithium aluminum hydride in THF reduces the azide andremoves the acyl group to give compound 98. Treatment with HCl removesboth the TBS group and the cyclic ketal to give compound 99. Olefinationusing methyltriphenylphosphonium bromide and KO^(t)Bu in THF givescompound 100. Treatment with acetic acid forms the ammonium acetate saltto give compound 101.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 90

A mixture of compound 60 (12.7 g, 22.4 mmol), K₂CO₃, (9.38 g, 67.2mmol), MeOH (250 mL) and water (94 mL) was stirred 55° C. for 2 hours,cooled to ambient temperature then concentrated. The residue wasdissolved in EtOAc, washed twice with saturated NaHCO₃ solution thentwice with brine, dried over anhydrous MgSO₄ and concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc) toafford compound 90 (10.16 g, 86%) as a white foam.

Synthesis of Compound 91

To a solution of compound 90 (10.14 g, 19.3 mmol) in pyridine (50 mL) at0° C. was added methanesulfonyl chloride (2.69 mL, 34.8 mmol). Themixture was stirred at 0° C. for 10 minutes, then at ambient temperaturefor 2 hours. The mixture was diluted with EtOAc (200 mL) and washed withwater (2×50 mL). The combined aqueous portions were back-extracted withEtOAc (50 mL). The combined organics were washed with brine (2×50 mL),dried over anhydrous MgSO₄ and concentrated.

The residue was dissolved in toluene and concentrated to give compound91 (11.3 g, 97%) as a white foam which was used for the next reactionwithout further purification.

Synthesis of Compound 92

To a stirred mixture of diphenyl diselenide (7.04 g, 22.1 mmol) and EtOH(100 mL) at 0° C., NaBH₄ (1.69 g, 44.2 mmol) was added portionwise over7 minutes, then after 5 minutes the mixture was allowed to warm toambient temperature and stirred for an additional hour. The resultingsolution was added via cannula to a slurry of compound 91 in EtOH (175mL), rinsing with EtOH (25 mL). The mixture was stirred at 50° C. for 35minutes. The mixture was cooled, water (70 mL) was added and the mixturewas concentrated. The residue was dissolved in EtOAc (400 mL) and washedwith water (100 mL), then brine (100 mL). The combined aqueous washeswere back-extracted with EtOAc (3×75 mL). The combined organics werewashed with brine (2×100 mL), dried over anhydrous MgSO₄ andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc) to afford compound 92 (10.6 g, 87%) as a yellow foam.

Synthesis of Compound 93

A mixture of compound 92 (10.2 g, 15.4 mmol) and 30% H₂O₂ solution inTHF (4500 mL) was stirred at ambient temperature for 50 minutes then at65° C. for 40 minutes. After cooling, the mixture was diluted with EtOAc(500 mL) and washed with brine (200 mL), then saturated NaHCO₃ solution(200 mL). The combined aqueous portions were back-extracted with EtOAc(2×100 mL). The combined organic portions were washed with brine (2×200mL), dried over anhydrous MgSO₄ and concentrated.

The residue was purified by chromatography on silica gel (hexanes/EtOAc,3:1; EtOAc) to afford compound 93 (5.86 g, 75%) as a white foam.

Synthesis of Compound 94

To a solution of compound 93 (4.81 g, 9.49 mmol) in THF (90 mL), tBuOH(30 mL) and water (9 mL) were added NMO (1.72 g, 14.2 mmol) and OsO₄(3.0 mL of a 4% solution in water, 0.47 mmol). The reaction mixture wasstirred at ambient temperature overnight, then a solution ofNa₂S₂O₃.5H₂O (1.75 g) in water (30 mL) was added. The mixture wasstirred for 30 minutes then diluted with brine (350 mL) and extractedwith CH₂Cl₂ (200 mL, 2×125 mL, 75 mL). The combined organics were washedwith brine (2×150 mL), dried over anhydrous MgSO₄ and concentrated togive compound 94 (5.70 g) as a light brown foam which was used for thenext reaction without further purification.

Synthesis of Compound 95

To a solution of compound 94 (5.70 g) in CH₂Cl₂ (100 mL) was addedPb(OAc)₄ (4.43 g, 9.49 mmol). The reaction mixture was stirred atambient temperature for 35 minutes, then filtered through a silica plugand concentrated. The residue was purified by chromatography on silicagel (hexanes/EtOAc, 9:1, 4:1) to afford compound 95 (4.21 g, 85% fromINT1660) as a white foam.

Synthesis of Compound 96

To a stirred solution of compound 95 (300 mg, 0.59 mmol) in a mixture ofMeOH/THF (2 mL/7 mL) at 0° C. was added NaBH₄ (45 mg, 1.2 mmol). After 5min at 0° C., the mixture was stirred at ambient temperature andadditional NaBH₄ (89 mg, 2.4 mmol) was added in portions over 4 hours.The mixture was cooled to 0° C. and the reaction was quenched by water(1 mL). The mixture was diluted with EtOAc (200 mL), washed twice withbrine, dried and concentrated. The residue was purified by columnchromatography (hexanes/EtOAc, 6:4) to afford compound 96 in 82% yield.

Synthesis of Compound 97

Using the methods described in the Method B procedure in Example 12below for the synthesis of compound 116, compound 97 was prepared fromcompound 96. The crude compound 97 was subjected to columnchromatography (hexanes/EtOAc, 8:2), and used in next step withoutfurther purification.

Synthesis of Compound 98

To a stirred solution of impure compound 97 (0.59 mmol) in THF (20 mL)at 0° C. was added 1M LAH in THF (5.8 mL, 5.8 mmol) dropwise. After 25min at 0° C., the mixture was stirred at ambient temperature for 3hours. The mixture was cooled to 0° C. again and solid Na₂SO₄.10H₂O(1.86 g, 5.8 mmol) was added portionwise. The mixture was stirred at 0°C. for 5 min and then at ambient temperature for another 20 min beforefiltration through Celite. The filtrate was concentrated and the residuewas purified by column chromatography (EtOAc/MeOH/Et₃N, 9:1:0.5) toafford compound 98 (150 mg, 59% from compound 96) as a clear gum.

Synthesis of Compound 99

A mixture of compound 98 (150 mg, 0.32 mmol) and 80% HOAc (5 mL) wasstirred at 40° C. for 7 hours. The solvents were removed by rotaryevaporation and dried in vacuum. The crude compound 99 was used in nextstep without purification.

Synthesis of Compound 100

A mixture of MePPh₃Br (1.26 g, 3.5 mmol) and KO^(t)Bu (395 mg, 3.5 mmol)in THF (15 mL) was stirred at ambient temperature for 2 hours and thenadded to a mixture of compound 99 obtained above in THF (5 mL) and DMF(1 mL). The reaction mixture was stirred at ambient temperature for 2days and then quenched with saturated NH₄Cl (0.25 mL). The mixture wasdiluted with EtOAc (20 mL) and MeOH (5 mL) and filtered through Celite.The filtrate was concentrated and the residue was purified by columnchromatography (EtOAc/MeOH/water/Et₃N, 6:3:0.5:0.5) to yield compound100 (47 mg, 47% from compound 98).

Synthesis of Compound 101

A solution of compound 100 (47 mg, 0.15 mmol) in 80% HOAc was stirred atambient temperature for a few minutes and then the solvents were removedby rotary evaporation. The residue was co-evaporated with MeOH severaltimes. The residue was dissolved in a small amount of MeOH and treatedwith a small amount of acetonitrile. The product was precipitated outand the supernatant was removed with pipette. The solid obtained wasdried in vacuum to afford compound 101 (35 mg, 62%) as a pale powder:LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 308.06; C₁₉H₃₄NO₂.

Example 11

Compounds 107-108, representative compounds of the invention, may beprepared according to the following Reaction Scheme 11. Any number ofcompounds related to compounds 107-108 could be produced using similarmethodology. Starting compound 33 may be prepared according toprocedures described above in Example 3.

In general, the free hydroxyl is reacted to give the mesylate compound102 using MsCl and pyridine. Azide displacement of the mesylate usingsodium azide in DMF gives compound 103. Sodium borohydride selectivelyreduces the carbonyl to give compound 104. Reduction of the azide usingPPh₃ and water in THF gives compound 105. Treatment with HCl removes theTBS group and the cyclic ketal to give compound 106. Olefination usingMePPh₃Br and KO^(t)Bu in THF gives compound 107. Treatment with aceticacid forms the ammonium acetate salt to give compound 108.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 102

To a solution of compound 33 (15.0 g, 31.2 mmol) in pyridine (100 mL) at00° C. was added methanesulfonyl chloride (4.35 mL, 56.2 mmol). Thereaction mixture was stirred at 0° C. for 10 minutes, then at ambienttemperature for 4 hours. The mixture was diluted with EtOAc (400 mL),washed with water (2×100 mL) and then brine (2×100 mL), then dried overanhydrous MgSO₄ and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 3:1, 1:1) to give compound102 (12.8 g, 78%) as a white foam.

Synthesis of Compound 103

A mixture of compound 102 (0.800 g, 1.43 mmol) and NaN₃ (0.190 g, 2.89mmol) in dry DMF (15 mL) was stirred at 50° C. for 3 hours, then at 40°C. overnight. After cooling to ambient temperature, the mixture wasdiluted with water (80 mL) and extracted with Et₂O (3×30 mL). Theorganic portion was washed with brine (2×20 mL), dried over anhydrousMgSO₄ and concentrated. The residue was purified by chromatography onsilica gel (hexanes; hexanes/EtOAc, 19:1, 9:1, 4:1) to give compound 103(0.476 g, 66%) as a yellow oil.

Synthesis of Compound 104

To a stirred solution of compound 103 (0.473 g, 0.935 mmol) in THF (15mL) and MeOH (5 mL) at 0° C. was added NaBH₄ (0.286 g, 7.48 mmol) inportions over 5 minutes. The resulting mixture was stirred at 0° C. for10 minutes then at ambient temperature overnight. The reaction wasquenched with water (50 mL), then extracted with EtOAc (30 mL, 2×20 mL).The organic extracts were washed with brine (2×20 mL), dried overanhydrous MgSO₄ and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 9:1, 4:1) to give compound104 (0.349 g, 73%) as a white foam.

Synthesis of Compound 105

A mixture of compound 104 (0.346 g, 0.681 mmol), PPh₃ (0.542 g, 2.04mmol), water (1 mL) and THF (20 mL) was stirred at 40° C. overnight andthen concentrated. The residue was purified by chromatography on silicagel (CH₂Cl₂/MeOH, 19:1; CH₂Cl₂/MeOH/Et₃N, 9:1:0.2) to give compound 105(0.336 g, quantitative) as a colourless glass.

Synthesis of Compound 106

A mixture of compound 105 (0.050 g, 0.10 mmol) and 2 N HCl (1 mL, 2mmol) in THF (3 mL) was stirred at ambient temperature for 2 hours, thenconcentrated. To a solution of the residue in CH₂Cl₂/MeOH (1:1, 8 mL)was added macroporous polystyrene-bound carbonate (0.105 g, 0.300 mmol)and the mixture was stirred at ambient temperature for 3 hours. Themixture was filtered, rinsing with CH₂Cl₂/MeOH (1:1, 3×5 mL) and thefiltrate was concentrated to give compound 106 (0.032 g, 94%) as acolourless oil.

Synthesis of Compound 107

A mixture of KO^(t)Bu (0.339 g, 2.87 mmol) and MePPh₃Br (1.02 g, 2.87mmol) in THF (12 mL) was stirred at ambient temperature for 2.5 hours,then a solution of compound 106 (0.116 g, 0.359 mmol) in THF (6 mL) andDMF (2 mL) was added. The reaction mixture was stirred at ambienttemperature overnight, then quenched with saturated NH₄Cl solution (4mL), diluted with MeOH (10 mL), filtered and the filtrate wasconcentrated. The residue was washed with EtOAc (3×10 mL) and MeOH (2×10mL). The combined washes were concentrated. The residue was purified bychromatography on silica gel (EtOAc/MeOH; EtOAc/MeOH/H₂O/Et₃N) to affordcompound 107 (0.024 g, 21%) as a colourless glass.

Synthesis of Compound 108

A mixture of compound 107 (0.035 g, 0.11 mmol) and 80% acetic acid (5mL) was stirred at ambient temperature for 45 minutes, thenconcentrated. The residue was dissolved in MeOH and concentrated threetimes. Precipitation from ACN/MeOH gave compound 108 (0.036 g, 86%) as ayellow solid: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 322.24; C₂₀H₃₆NO₂.

Example 12

Compounds 119-120, representative compounds of the invention, may beprepared according to the following Reaction Scheme 12. Any number ofcompounds related to compounds 119-120 could be produced using similarmethodology. Starting compound 102 may be prepared according toprocedures described above in Example 11.

In general, mesylate displacement by phenylselenide gives compound 109.Oxidative elimination using hydrogen peroxide gives the olefin compound110. Sodium borohydride reduction gives the alcohol compound III.Reaction with acetic anhydride and DMAP in pyridine gives compound 112.Ozonation gives the aldehyde compound 113. Sodium borohydride reductiongives compound 114. The free hydroxyl is reacted to give the mesylatecompound 115 using MsCl and pyridine. Azide displacement of the mesylateusing sodium azide in DMF gives compound 116. Reaction with lithiumaluminum hydride in THF reduces the azide and removes both the acylgroup and the TBS group to give compound 117. Treatment with HCl removedthe cyclic ketal to give compound 118. Olefination using MePPh₃Br andKO^(t)Bu in THF gave compound 119. Treatment with acetic acid forms theammonium acetate salt to give compound 120.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 109

To a stirred mixture of diphenyl diselenide (7.25 g, 22.8 mmol) and EtOH(100 mL) at 0° C. NaBH₄ (1.74 g, 45.5 mmol) was added portionwise, after5 minutes the mixture was allowed to warm to ambient temperature andstirred for an additional hour.

The resulting solution was added via cannula to a slurry of compound 102in EtOH (175 mL), rinsing with EtOH (25 mL). The mixture was stirred atambient temperature for 30 minutes then at 50° C. for 45 minutes. Themixture was cooled, water (80 mL) was added and the mixture wasconcentrated. The residue was dissolved in EtOAc (500 mL) and washedwith brine (2×100 mL). The combined aqueous washes were back-extractedwith EtOAc (200 mL) and the EtOAc portion was washed with brine (2×50mL). The combined organic extracts were dried over anhydrous MgSO₄ andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc, 9:1) to afford compound 109 (8.9 g, 75%) as a lightyellow solid.

Synthesis of Compound 110

A mixture of compound 109 (0.907 g, 1.46 mmol) and 30% H₂O₂ solution inTHF (60 mL) was stirred at ambient temperature for 1 hour then at 65° C.for 1 hour. After cooling, the mixture was diluted with EtOAc (60 mL)and washed with brine (30 mL), then saturated NaHCO₃ solution (40 mL).The combined aqueous portions were back-extracted with EtOAc (2×20 mL).The combined organic portions were washed with brine (2×40 mL), driedover anhydrous MgSO₄ and concentrated. The residue was purified bychromatography on silica gel (hexanes; hexanes/EtOAc, 7:1) to affordcompound 110 (0.447 g, 66%) as a white solid.

Synthesis of Compound 111

To a stirred solution of compound 110 (3.82 g, 8.26 mmol) in THF (75 mL)and MeOH (25 mL) at 0° C. was added NaBH₄ (1.06 g, 27.7 mmol) inportions over 20 minutes. The resulting mixture was stirred at 0° C. for10 minutes, then at ambient temperature overnight. The reaction wascooled to 0° C. and quenched with water (200 mL), then extracted withEtOAc (3×100 mL). The organic extracts were washed with brine (2×100mL), dried over anhydrous MgSO₄ and concentrated to afford compound III(3.76 g, 98%) as a white foam.

Synthesis of Compound 112

To a solution of compound III (5.36 g, 11.5 mmol) and DMAP (0.282 g,2.31 mmol) in pyridine (85 mL) was added acetic anhydride (10.9 mL, 115mmol). The resulting mixture was stirred at 50° C. overnight, thencooled to ambient temperature, diluted with EtOAc (350 mL) and washedwith water (120 mL). The aqueous portion was back-extracted with EtOAc(2×50 mL). The combined organics were washed with brine (2×125 mL),dried over anhydrous MgSO₄ and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 9:1) to afford compound 112(5.37 g, 92%) as a white foam.

Synthesis of Compound 113

A solution of compound 112 (4.84 g, 9.55 mmol) in CH₂Cl₂ (75 mL) andMeOH (25 mL) was treated with ozone at −78° C. for 3.5 hours. Nitrogenwas bubbled at −78° C. for 10 minutes, then dimethyl sulfide (12 mL, 164mmol) was added and the mixture was stirred at −78° C. for 10 minutes,then at ambient temperature for 2 hours.

The mixture was concentrated, then the residue was dissolved in EtOAc(200 mL), washed with water (2×50 mL) and then brine (2×50 mL), driedover anhydrous MgSO₄ and concentrated to afford compound 113 (4.59 g,94%) as a white foam.

Synthesis of Compound 114

To a stirred solution of compound 113 (300 mg, 0.59 mmol) in a mixtureof MeOH/THF (2 mL/7 mL) at 0° C. was added NaBH₄ (64 mg, 1.7 mmol).After 15 min at 0° C., the mixture was stirred at ambient temperaturefor 1 hour and then additional NaBH₄ (20 mg, 0.53 mmol) was added. Themixture was stirred for another 50 min before cooled to 0° C. and thereaction was quenched by water (5 mL). The mixture was diluted withEtOAc (200 mL), washed twice with brine, dried and concentrated toafford crude compound 114 (299 mg, 99%). The product was used in nextstep without purification.

Synthesis of Compound 115

To a stirred solution of compound 114 (103 mg, 0.2 mmol) in pyridine at0° C. was added MsCl (0.1 mL, 0.9 mmol) dropwise. The resulting mixturewas stirred at ambient temperature for 8 hours, then diluted with EtOAc(200 mL), washed with brine, dried and concentrated to give crudecompound 115, which was used in next step without purification.

Synthesis of Compound 116 Method A

A mixture of compound 115 obtained above and NaN₃ (46 mg, 0.7 mmol) inDMF (1.6 mL) was stirred at 60° C. overnight. The reaction mixture wasdiluted with toluene (150 mL) and washed with brine. The aqueouswashings were combined and extracted with toluene. The organic extractswere combined and washed with brine, dried and concentrated. The residuewas purified by column chromatography on silica gel (hexanes/EtOAc, 9:1)to afford compound 116 (45 mg, 43% from INT1861) as a pale gum.

Method B

To a stirred solution of compound 114 (293 mg, 0.57 mmol) in THF (6 mL)at 0° C. were added Ph₃P (329 mg, 1.25 mmol), DIAD (0.25 mL, 1.27 mmol),and DPPA (0.27 mL, 1.25 mmol). After 10 min at 0° C., the mixture wasstirred at ambient temperature overnight. The reaction was quenched bywater (20 mL), and extracted with EtOAc. The EtOAc extracts werecombined and washed with saturated NaHCO₃, brine, dried andconcentrated. The residue was purified by column chromatography(hexanes/EtOAc, 9:1) to yield compound 116 (275 mg, 89%) as a pale gum.

Synthesis of Compound 117

To a stirred solution of compound 116 (128 mg, 0.24 mmol) in THF (5 mL)at 0° C. was added 1M LAH in THF (0.95 mL, 0.95 mmol) dropwise. After 10min at 0° C., the mixture was stirred at ambient temperature for 4.5hours. The mixture was cooled to 0° C. again and solid Na₂SO₄.10H₂O (308mg, 0.95 mmol) was added portionwise.

The mixture was stirred at 0° C. for 10 min and then at ambienttemperature for another min before filtration through Celite. Thefiltrate was diluted with EtOAc (200 mL), washed with brine, dried(Na₂SO₄) and concentrated. The residue was purified by columnchromatography (EtOAc/MeOH/water/Et₃N, 7:2:0.5:0.5) to afford compound117 (45 mg, 53%).

Synthesis of Compound 118

A mixture of compound 117 (45 mg, 0.13 mmol) and 2N HCl (1 mL) in THF (3mL) was stirred at ambient temperature overnight. The solvents wereremoved by rotary evaporation and the residue was purified by columnchromatography (EtOAc/MeOH/water/Et₃N, 7:2:0.5:0.5) to give compound 118(50 mg, with traces of Et₃N).

Synthesis of Compound 119

A mixture of MePPh₃Br (457 mg, 1.28 mmol) and KO^(t)Bu (144 mg, 1.28mmol) in THF (6 mL) was stirred at ambient temperature for 1 hour 40 minand then added to a mixture of compound 118 (50 mg, 0.16 mmol) in THF (3mL) and DMF (1 mL). The reaction mixture was stirred at ambienttemperature overnight and then quenched with saturated NH₄Cl (2 mL).After being stirred for a few minutes, the mixture was concentrated byrotary evaporation. The residue paste was repeatedly extracted withEtOAc and filtered. The filtrates were combined and concentrated. Theresidue was purified by column chromatography (EtOAc/MeOH/water/Et₃N,7:2:0.5:0.5) to yield compound 119 (24 mg, 63% from compound 117).

Synthesis of Compound 120

To a stirred solution of compound 119 (43 mg) in MeOH (˜2 mL) was added80% HOAc (0.5 mL) and then the mixture was concentrated to dryness. Theresidue was re-dissolved in a small amount of MeOH and treated with asmall amount of acetonitrile. The mixture was concentrated again and theresulting precipitate was dried in vacuum to afford compound 120 (53 mg,100%) as a pale powder: LC/MS (direct infusion, electrospray +ve, 10 mMNH₄OAc in 3:7 water and MeCN) 308.11; C₁₉H₃₄NO₂.

Example 13

Compounds 132-133, representative compounds of the invention, may beprepared according to the following Reaction Scheme 13. Any number ofcompounds related to compounds 132-133 could be produced using similarmethodology. The starting compound 121 was prepared according to theprocedures described in U.S. Pat. No. 6,046,185.

In general, olefination using (EtO)₂P(O)CHF₂ and lithiumdiisopropylamide (LDA) in THF gives compound 122. Tetrabutylammoniumfluoride in THF removes the TBS group to give compound 123. Reactionwith acetic anhydride in pyridine gives compound 124. Treatment with 80%acetic acid removes the acetonide group to give compound 125. NaIO₄oxidation gives the dialdehyde compound 126. Sodium borohydridereduction gives compound 127. Reaction with acetic anhydride in pyridinegives compound 128. The free hydroxyl is reacted to give the mesylatecompound 129 using MsCl and pyridine. Azide displacement of the mesylateusing sodium azide in DMF gives compound 130. Reduction of the azideusing PPh₃ and water in THF gives compound 131. Methanolysis of theacetates gives compound 132. Treatment with HCl forms the salt compound133.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 122

Freshly prepared LDA (3.4 mL, 2.4 mmol) was added to a −78° C. solutionof F₂CHPO(OEt)₂ (0.40 mL, 2.5 mmol) in dry THF (3 mL) under argon. After20 minutes, a solution of compound 121 (0.30 g, 0.63 mmol) in dry THFwas added. The reaction was continued for 1 hour, then slowly warmed toambient temperature over 2 hours and finally was heated at 60° C. for 3hours. The reaction was cooled to ambient temperature, then quenched by0.5 mL of water. The solution was diluted with EtOAc and was washed withbrine, then dried over MgSO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel (4% EtOAc/hexanes) toafford compound 122 (0.145 g, 45%) as a white solid.

Synthesis of Compound 123

A solution of compound 122 (0.65 g, 1.3 mmol), Bu₄NF (2.7 ml of a 1Msolution in THF) and THF (10 ml) was heated at 50° C. for 3 hours. Thereaction mixture was concentrated and the residue was purified by columnchromatography on silica gel (30% EtOAc/hexanes) to afford compound 123(0.54 g, quantitative).

Synthesis of Compound 124

A solution of compound 123 (0.54 g, 1.3 mmol), acetic anhydride (0.24mL, 2.5 mmol) and pyridine (5 mL) was stirred at ambient temperature for3 days. The solution was diluted with EtOAc, was washed with brine, thendried over MgSO₄, filtered and concentrated. The crude compound 124 wasused in the next step without further purification.

Synthesis of Compound 125

A solution of compound 124 (crude, 1.3 mmol) and 80% acetic acid (10 mL)was heated at 50° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure and the residual solvents were removed bycodistillation with toluene.

The crude compound 125 was used in the next step without furtherpurification.

Synthesis of Compound 126

A solution of NaIO₄ (0.54 g, 2.5 mmol) and water (4 mL) was added to asolution of compound 125 (crude, 1.3 mmol) and THF (10 mL). After 3hours the solution was diluted with CH₂Cl₂ and washed with brine, thendried over MgSO₄, filtered and concentrated. The crude compound 126 wasused in the next step without further purification.

Synthesis of Compound 127

Sodium borohydride (48 mg, 1.3 mmol) was added to a solution of compound126 (crude, 1.3 mmol), THF (6 mL) and MeOH (2 mL). After 3 hours, thereaction was quenched by water (15 mL) and the solution was extractedusing 2×15 mL of EtOAc. The combined extracts were dried over MgSO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel (30% EtOAc/hexanes) to afford compound 127(0.38 g, 75%) as a white solid.

Synthesis of Compound 128

A solution of compound 127 (0.38 g, 0.95 mmol), acetic anhydride (0.09mL, 1 mmol) and pyridine (5 mL) was stirred overnight at ambienttemperature. The reaction mixture was diluted with water and extractedwith 2×15 mL of EtOAc. The combined extracts were dried over MgSO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel to afford compound 128 (0.32 g, 76%) as awhite solid.

Synthesis of Compound 129

A solution of compound 128 (0.32 g, 0.72 mmol), MsCl (0.11 mL, 1.4 mmol)and pyridine (5 mL) was stirred at ambient temperature for 3 hours. Thereaction mixture was quenched with water and was extracted with EtOAc(2×25 mL). The combined extracts were washed with brine then were driedover MgSO₄, filtered and concentrated. The crude compound 129 was usedin the next step without further purification.

Synthesis of Compound 130

A solution of compound 129 (crude, 0.72 mmol), NaN₃ (0.83 g, 3.6 mmol)and DMF (5 mL) was heated overnight at 55° C. The reaction mixture wascooled to ambient temperature and was diluted with water (10 mL), thenextracted with toluene.

The toluene solution was dried over MgSO₄, filtered and concentrated.The residue was purified by column chromatography on silica gel (20%EtOAc/hexanes) to afford compound 130 (0.30 g, 89%) as a white foam.

Synthesis of Compound 131

A solution of compound 130 (0.13 g, 0.28 mmol), PPh₃ (0.15 g, 0.56mmol), THF (3 mL) and water (0.3 mL) was stirred under argon for 3 days.The reaction mixture was concentrated and the residue was purified bycolumn chromatography on silica gel (EtOAc/MeOH/Et₃N 9:1:0.5) to affordcompound 131 (98 mg, 79%) as a white solid.

Synthesis of Compound 132

A solution of compound 131 (0.28 g, 0.65 mmol), NaOMe (0.5 mL of a 25%solution in MeOH) and MeOH (5 mL) was stirred at ambient temperature for3 hours. The reaction mixture was concentrated and the residue waspurified by column chromatography (EtOAc/MeOH/NH₄OH 9:1:0.6) to affordcompound 132 (0.21 g, 89%) as a white solid.

Synthesis of Compound 133

A solution of compound 132 (0.24 g, 0.68 mmol), HCl (1.36 mL of a 1Msolution in Et₂O) and MeOH (3 mL) was stirred at ambient temperature for30 minutes.

The reaction mixture was concentrated and the residue was triturate inEtOAc (5 mL).

The resulting white solid was filtered and dried overnight under highvacuum at 56° C. to afford compound 133 (0.21 g, 78%): LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 358.14;C₂₀H₃₄F₂NO₂.

Example 14

Compound 143, a representative compound of the invention, may beprepared according to the following Reaction Scheme 14. Any number ofcompounds related to compound 143 could be produced using similarmethodology. Starting compound 121 may be prepared by the proceduresdescribed in U.S. Pat. No. 6,046,185.

In general, olefination using (EtO)₂P(O)CCl₃ and LDA in THF givescompound 134. Treatment with 80% acetic acid removes both the TBS groupand the acetonide group to give compound 135. Treatment with TBSCl andimidazole in DMF selectively protects one hydroxyl to give compound 136.NaIO₄ oxidation gives the dialdehyde compound 137. Sodium borohydridereduction gives compound 138. Treatment with TBSCl and imidazole in DMFselectively protects one hydroxyl to give compound 139. The freehydroxyl is reacted to give the mesylate compound 140 using MsCl andpyridine. Azide displacement of the mesylate using sodium azide in DMFgives compound 141. Reduction of the azide using PPh₃ and water in THFgives compound 142. Treatment with HCl removes the TBS groups and formsthe salt compound 143.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 134

CCl₃P(O)(OEt)₂ (1.12 ml, 6 mmol) was added to a −78° C. solution offreshly prepared LDA (6 mmol) in dry THF (20 mL) under argon. After 5minutes a compound 121 (954 mg, 2 mmol) was added. The reaction wascontinued for 1 hour, then slowly warmed to ambient temperature over 2hours and finally was stirred at ambient temperature for overnight. Thereaction quenched by 0.5 mL of water. The solution was diluted withEtOAc and was washed with water, then dried over MgSO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (3% EtOAc/hexanes) to afford compound 134 (109 mg, 10%) as apale yellow foam.

Synthesis of Compound 135

A solution of compound 134 (288 mg, 0.53 mmol) in 2 ml THF and 80%acetic acid (8 mL) was heated at 50° C. for 2 hours. The reactionmixture was concentrated under reduced pressure and the residualsolvents were removed by codistillation with toluene. The crude compound135 was used in the next step without further purification.

Synthesis of Compound 136

A solution of compound 135 (crude, 0.53 mmol) in DMF (3 mL), imidazole(108 mg, 1.6 mmol) and TBSCl (160 mg, 1.1 mmol) was stirred at ambienttemperature for 2 hours. The reaction mixture was diluted with 50 mlwater and extracted with 100 mL of EtOAc. The extracts were dried overMgSO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel to afford compound 136 (243 mg, 91%) as apale yellow foam.

Synthesis of Compound 137

A solution of NaIO₄ (205 mg, 0.96 mmol) and water (2 mL) was added to asolution of compound 136 (243 mg, 0.48 mmol) and THF (6 mL). After 3hours the solution was diluted with CH₂Cl₂ and washed with brine, thendried over MgSO₄, filtered and concentrated. The crude compound 137 wasused in the next step without further purification.

Synthesis of Compound 138

Sodium borohydride (36 mg, 0.96 mmol) was added to a solution ofcompound 137 (crude, 0.48 mmol), THF (3 mL) and MeOH (1 mL). After 3hours, the reaction was quenched by water (30 mL) and the solution wasextracted using 2×50 mL of EtOAc. The combined extracts were dried overMgSO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (30% EtOAc/hexanes) to afford compound 138(201 mg, 83%) as pale yellow oil.

Synthesis of Compound 139

A solution of compound 138 (201 mg, 0.4 mmol), imidazole (136 mg, 2mmol), TBSCl (110 mg, 0.73 mmol) and DMF (3 mL) was stirred for 1 hourat ambient temperature. The reaction mixture was diluted with 30 mLwater and extracted with 2×40 mL of EtOAc. The combined extracts weredried over MgSO₄, filtered and concentrated. The residue was purified bycolumn chromatography on silica gel to afford compound 139 (230 mg, 93%)as pale yellow oil.

Synthesis of Compound 140

A solution of compound 139 (216 mg, 0.35 mmol), MsCl (0.14 mL, 1.8 mmol)and pyridine (3.5 mL) was stirred at ambient temperature for 2 hours.The reaction mixture was quenched with 30 mL water and was extractedwith EtOAc (2×40 mL). The combined extracts were washed with brine thenwere dried over MgSO₄, filtered and concentrated. The crude compound 140was used in the next step without further purification.

Synthesis of Compound 141

A solution of compound 140 (crude, 0.35 mmol), NaN₃ (178 mg, 2.7 mmol)and DMF (3 mL) was heated overnight at 55° C. The reaction mixture wascooled to ambient temperature and was diluted with water (30 mL), thenextracted with toluene.

The toluene solution was dried over MgSO₄, filtered and concentrated.The residue was purified by column chromatography on silica gel (5%EtOAc/hexanes) to afford compound 141 (202 mg, 89%) as pale yellow oil.

Synthesis of Compound 142

A solution of compound 141 (202 mg, 0.31 mmol), PPh₃ (320 mg, 1.2 mmol),THF (4 mL) and water (0.3 mL) was stirred under argon overnight, thenheated at 50° C. for 4 hours. The reaction mixture was concentrated andthe residue was purified by 2 g SCX ion-exchange (6 volume MeOH, 3volume 5% ammonia/MeOH) to afford compound 142 as a pale yellow foam(TBS group lost partially during this process).

Synthesis of Compound 143

A solution of compound 142 (crude, 0.31 mmol), HCl (1 mL of a 1Msolution in Et₂O), THF (3 mL) and water (0.5 mL) was stirred at ambienttemperature for 2 hours. The reaction mixture was kept at 4° C. for 1hour. The resulting white solid was filtered and washed with EtOAc, thendried overnight under high vacuum at 56° C. to afford compound 143 (122mg, 92%): LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7water and MeCN) 390.06; C₂₀H₃₄Cl₂NO₂.

Example 15

Compounds 157-158, representative compounds of the invention, may beprepared according to the following Reaction Scheme 15. Startingcompound 144 may be prepared according to the procedures outlined inU.S. Pat. No. 6,046,185. Any number of compounds related to compounds157-158 could be produced using similar methodology.

In general, reaction of compound 144 with TBSCl and imidazole in DMFgives compound 145. Hydroboration with borane-tetrahydrofuran complex inTHF, followed by oxidative workup with NaOH and H₂O₂ converts compound145 to the secondary alcohol compound 146. Oxidation with a catalyticamount of tetra-n-propylammonium perruthenate (TPAP) and NMO in CH₂Cl₂gives compound 147. Olefination with MePPh₃Br and KO^(t)Bu in THF givesalkene 148. Tetrabutylammonium fluoride removes the TBS group to givecompound 149. Reaction with acetic anhydride in pyridine gives compound150. Treatment with 80% acetic acid removes the acetonide group to givecompound 151. NaIO₄ oxidation gives the dialdehyde compound 152. Sodiumborohydride reduction gives compound 153. Reaction with acetic anhydridein pyridine selectively protects one hydroxyl to give compound 154. Thefree hydroxyl is reacted to give the mesylate compound 155 using MsCland pyridine. Azide displacement of the mesylate using sodium azide inDMF gives compound 156. Reaction with lithium aluminum hydride in THFreduces the azide and removes the acetates to give compound 157.Treatment with 80% acetic acid forms the ammonium acetate salt compound158.

Synthesis of Compound 145

A solution of compound 144 (10.0 g, 26.7 mol), TBSCl (6.22 g, 40.1mmol), and imidazole (3.67 g, 53.4 mmol) in dry DMF (178 mL) was stirredat ambient temperature for 2.5 hours. The reaction mixture was dilutedwith water (250 mL) and extracted with toluene (3×250 mL). The combinedtoluene extracts were washed with brine (250 mL), dried over MgSO₄,filtered, and concentrated. The crude compound 145 (12.5 g, 96%) wasused in the next reaction without further purification.

Synthesis of Compound 146

To a solution of compound 145 (12.5 g, 25.6 mmol) in dry THF (150 mL)was added borane-tetrahydrofuran complex (46 mL of 1.0 M solution inTHF) and the reaction mixture was stirred at ambient temperature for 1hour. 10% aqueous NaOH (180 mL) was slowly added. The mixture was cooledin ice and 30% aqueous solution of H₂O₂ (120 mL) was slowly added. Themixture was stirred at ambient temperature for hour and then extractedwith EtOAc (3×250 mL). The combined EtOAc extracts were washed with 10%aqueous Na₂S₂O₃ (200 mL), brine (200 mL), dried over MgSO₄, filtered,and concentrated. The residue was purified by chromatography on silicagel (CH₂Cl₂/EtOAc, 95:5 then 85:15 and hexanes/EtOAc, 90:10 then 85:15)to afford compound 146 (10.7 g, 83%) as a white solid.

Synthesis of Compound 147

To a mixture of compound 146 (8.50 g, 16.8 mmol), NMO (2.23 g, 18.5mmol), 4 Å molecular sieves (5.3 g) in CH₂Cl₂ (85 mL) was added TPAP(152 mg, 0.42 mmol). The reaction mixture was stirred at ambienttemperature for 1 hour, then filtered through silica gel packed in asintered glass funnel (eluted with hexanes/EtOAc, 1:1), and concentratedto dryness. The crude product 147 was used in the next reaction withoutfurther purification.

Synthesis of Compound 148

A mixture of KO^(t)Bu (5.69 g, 48.1 mmol) and MePPh₃Br (17.2 g, 48.1mmol) in THF (160 mL) was stirred at ambient temperature for one hourunder argon then compound 147 (8.10 g, 16.1 mmol) was added. Thereaction mixture was stirred at ambient temperature for 4 hours, dilutedwith brine (150 mL), extracted with EtOAc (3×200 mL). The combined EtOAcextracts were washed with brine (200 mL), dried over MgSO₄, filtered,and concentrated. The residue was purified by chromatography on silicagel (hexanes/EtOAc, 96:4 then 10:1 then 4:1) to afford compound 148 (6.3g, 79%) as a white foam.

Synthesis of Compound 149

A solution of compound 148 (6.3 g, 12.5 mmol) and n-Bu₄NF (18.8 mL of a1.0 M solution in THF) in THF (125 mL) was refluxed under argon for 1hour. Solvent was evaporated under reduced pressure and the residue waspurified by chromatography on silica gel (hexanes/EtOAc, 2:1 then 1:1)to afford compound 149 (4.8 g, 99%) as a white solid.

Synthesis of Compound 150

A solution of compound 149 (4.8 g, 12.4 mmol), acetic anhydride (2.3 mL,24.7 mmol) and DMAP (151 mg, 1.24 mmol) in pyridine (60 mL) was stirredat ambient temperature overnight. The reaction mixture was diluted withEtOAc (300 mL) and washed with brine (2×100 mL). The EtOAc layer wasdried over MgSO₄, filtered, and concentrated. The crude compound 150 wasused directly in the next step.

Synthesis of Compound 151

A mixture of compound 150 (crude, 12.4 mmol) and 80% acetic acid (90 mL)was stirred at 40° C. for 1 hour. The solution was concentrated toafford compound 151 that was used in the next step without furtherpurification.

Synthesis of Compound 152

A solution of compound 151 (2.20 g, 5.63 mmol), NaIO₄ (2.43 g, 11.3mmol), water (23 mL) and THF (46 mL) was stirred at ambient temperaturefor 3 hours. The reaction mixture was diluted with CH₂Cl₂ (200 mL) andwashed with brine (3×75 mL). The CH₂Cl₂ layer was dried over MgSO₄,filtered, and concentrated to afford compound 152 that was used in thenext step without further purification.

Synthesis of Compound 153

A solution of compound 152 (crude, 5.63 mmol), NaBH₄ (538 mg, 14.1mmol), THF (36 mL) and MeOH (12 mL) was stirred at 0° C. for 10 minutesthen at ambient temperature for 2 hours. The mixture was cooled in iceand 80% acetic acid (23 mL) was slowly added. The solution was stirredat ambient temperature for 10 minutes, then diluted with EtOAc (200 mL)and washed with brine (3×75 mL). The EtOAc layer was dried over MgSO₄,filtered, and concentrated to afford crude compound 153 that was used inthe next step without further purification.

Synthesis of Compound 154

A solution of compound 153 (crude, 5.63 mmol), acetic anhydride (0.58mL, 6.20 mmol) and DMAP (69 mg, 0.56 mmol) in pyridine (22 mL) wasstirred at ambient temperature for 1.5 hours. The reaction mixture wasdiluted with EtOAc (200 mL) and washed with brine (3×75 mL). The EtOAclayer was dried over MgSO₄, filtered, and concentrated. The residue waspurified by chromatography on silica gel (hexanes/EtOAc, 5:1 then 4:1then 7:3) to afford compound 154 (1.6 g, 65% for 5 steps).

Synthesis of Compound 155

To a solution of compound 154 (1.60 g, 3.68 mmol) in pyridine (15 mL)was added methanesulfonyl chloride (0.600 mL, 7.37 mmol) and thereaction mixture was stirred at ambient temperature for 4 hours. Thesolution was diluted with EtOAc (200 mL) and washed with brine (3×70mL), then dried over MgSO₄, filtered, and concentrated to afford crudecompound 155 that was used for the next reaction without furtherpurification.

Synthesis of Compound 156

A mixture of compound 155 (crude, 3.68 mmol) and NaN₃ (479 mg, 7.36mmol) in DMF (25 mL) was heated under argon at 60° C. overnight. Aftercooling, the reaction mixture was diluted with toluene (300 mL) and waswashed with brine (3×75 mL), then dried over MgSO₄, filtered, andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc, 9:1 then 8:2) to afford compound 156 (1.6 g, 95% for 2steps) as a white foam.

Synthesis of Compound 157

A solution of LiAlH₄ (13.9 mL of a 1.0 M solution in THF) was added toan ice cooled solution of compound 156 (1.60 g, 13.9 mmol) in THF (35mL) and stirred for minutes. The stirring was continued at ambienttemperature for 3 hours. The reaction mixture was cooled in ice,quenched with Na₂SO₄.10H₂O and stirred for 10 minutes. The mixture wasthen stirred for an additional 30 minutes at ambient temperature,diluted with EtOAc, and then filtered. The filtrate was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by chromatography on silica gel (EtOAc/MeOH/H₂O/Et₃N,70:20:10:0 then 70:20:10:3) to afford compound 157 (0.8 g, 66%) as awhite solid.

Synthesis of Compound 158

A solution of compound 157 (0.800 g, 2.29 mmol) and 80% acetic acid (20mL) was heated at 40° C. for 1 hour and, then concentrated. Residualsolvent was removed by codistillation with acetonitrile. The residue wastriturated in diethyl ether and filtered to give compound 158 (700 mg,75%) as a white solid. LC/MS (direct infusion, electrospray +ve, 10 mMNH₄OAc in 3:7 water and MeCN) 350.12; C₂₂H₄₀NO₂.

Example 16

Compound 163, a representative compound of the invention, may beprepared according to the following Reaction Scheme 16. Any number ofcompounds related to compound 163 could be produced using similarmethodology. Starting compound 21 may be prepared according to theprocedures described above in Example 1.

In general, treatment with 80% acetic acid removes the TBS group to givecompound 159. Reaction with TBSCl and imidazole in DMF gives compound160. Reaction with tosylhydrazine in toluene gives compound 161.Reaction with LDA gives the elimination product compound 162. Treatmentwith 80% acetic acid removes the TBS groups to give compound 163.

Synthesis of Compound 159

A mixture of compound 21 (1.19 g, 2.46 mmol) and 80% acetic acid (20 mL)was stirred at 55° C. for 3 hours then concentrated. The residue wasdissolved in toluene and concentrated three times. The residue waspurified by chromatography on silica gel (EtOAc/MeOH, 49:1) to givecompound 159 (0.747 g, 93%) as a white foam.

Synthesis of Compound 160

A mixture of compound 159 (0.747 g, 2.30 mmol), TBSCl (2.08 g, 13.8mmol) and imidazole (1.88 g, 27.6 mmol) in dry DMF (12 mL) was stirredat ambient temperature for 3 hours then diluted with water (50 mL) andextracted with EtOAc (3×50 mL). The combined organics were washed withbrine (2×30 mL), dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc,7:3) to give compound 160 (1.11 g, 93%) as a white foam.

Synthesis of Compound 161

A mixture of compound 160 (0.500 g, 0.904 mmol) and TsNHNH₂ (0.236 g,1.27 mmol) in toluene (20 mL) was heated at reflux for 1 hour, thenstirred at ambient temperature overnight, then heated at reflux foranother hour. After cooling, the mixture was concentrated. To theresidue was added CH₂Cl₂ and the mixture was cooled in ice.

The precipitate was filtered out, washing with cold CH₂Cl₂, then driedto afford compound 161 (0.588 g, 90%) as a white solid.

Synthesis of Compound 162

LDA solution was prepared by adding ^(n) BuLi (2 mL of a 2.5 M solutionin hexanes, 5.0 mmol) to a solution of ^(i)Pr₂NH (0.77 mL, 5.5 mmol) inTHF (4.23 mL) at 0° C., then stirring the solution at 0° C. for 30minutes. To a solution of compound 161 (0.550 g, 0.763 mmol) in THF (4mL) at ambient temperature was added LDA solution (6.4 mL of a 0.71 Msolution, 4.6 mmol). The reaction mixture was stirred at ambienttemperature overnight. The mixture was diluted with brine (50 mL) andextracted with EtOAc (3×50 mL). The combined organics were washed withbrine (2×30 mL), dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel (hexanes/EtOAc,19:1, 9:1) to give compound 162 (0.062 g, 15%) as a yellow gel.

Synthesis of Compound 163

A mixture of compound 162 (0.062 g, 0.11 mmol) and 80% acetic acid (2mL) was stirred at ambient temperature for 3 hours and thenconcentrated. The residue was dissolved in toluene and concentrated. Theresidue was purified by chromatography on silica gel (EtOAc/MeOH, 19:1)to give compound 163 (0.022 g, 65%) as a light yellow solid.

Example 17

Compound 178, a representative compound of the invention, may beprepared according to the following Reaction Scheme 17. Any number ofcompounds related to compound 178 could be produced using similarmethodology. Starting compound 164 may be prepared according to theprocedures outlined in U.S. Pat. No. 6,046,185.

In general, the free hydroxyl is reacted to give the mesylate compound165 using MsCl and pyridine. Treatment with LiBr and DBU in DMF givesthe elimination product compound 166. Osmolation gives the compound 167.Olefination using MePPh₃Br and KO^(t)Bu in THF gives compound 168.Reaction with acetic anhydride and DMAP in pyridine gives compound 169.Treatment with 80% acetic acid removes the acetonide group to givecompound 170. NaIO₄ oxidation gives the dialdehyde compound 171. Sodiumborohydride reduction gives compound 172. Treatment with TBSCl andimidazole in DMF selectively protects one hydroxyl to give compound 173.The free hydroxyl is reacted to give the mesylate compound 174 usingMsCl and pyridine. Azide displacement of the mesylate using sodium azidein DMF gives compound 175. Base hydrolysis of the acetates givescompound 176. Reduction of the azide using PPh₃ and water in THF givescompound 177. Treatment with 80% acetic acid removes the TBS group andforms the salt compound 178.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 165

To a solution of compound 164 (4.00 g, 11.03 mmol) in pyridine (20 mL)was added MsCl (1.28 mL, 16.55 mmol). The reaction mixture was stirredat ambient temperature for one hour under argon, then diluted with EtOAc(100 mL), washed with brine (2×50 mL), dried over anhydrous MgSO₄, andconcentrated to dryness. The crude product compound 165 used for thenext reaction without further purification.

Synthesis of Compound 166

A mixture of crude compound 165 (2.00 g, 4.54 mmol), lithium bromide(0.59 g, 6.81 mmol) and DBU (2 mL, 13.62 mmol) in dry DMF (50 mL) washeated at 150° C. for 1.5 hours. After cooling, toluene (120 mL) andwater (60 mL) were added to the reaction mixture. The layers wereseparated and the aqueous phase was extracted with toluene (80 mL). Thecombined toluene solution was washed with brine (100 mL), dried overanhydrous MgSO₄, and concentrated to dryness. The residue was purifiedby chromatography on silica gel (hexanes/EtOAc, 9/1) to afford impurecompound 166 (1.09 g, 70%) as a white solid.

Synthesis of Compound 167

To a solution of compound 166 (1.00 g, 2.90 mmol) in a mixture of THF(15 mL) and t-BuOH (5 mL) was added water (2.5 mL), followed by NMO(0.60 mL, 50% in H₂O) and OsO₄ (0.89 mL, 4% in H₂O). The reactionmixture was stirred at ambient temperature for 3 hours then a solutionof Na₂S₂O₃ (0.5 g) in water (15 mL) was added. The reaction mixture wasstirred for 20 minutes then extracted with CH₂Cl₂ (2×30 mL), washed withbrine (50 mL), dried over anhydrous MgSO₄, and concentrated to dryness.The residue was purified by chromatography on silica gel (hexanes/EtOAc,1:1) to afford compound 167 (0.65 g, 60%) as a white solid.

Synthesis of Compound 168

A mixture of KO^(t)Bu (2.88 g, 32.9 mmol) and MePPh₃Br (11.8 g, 32.9mmol) in THF (40 mL) was stirred at ambient temperature for 1 hour thencompound 167 (4.15 g, 11.0 mmol) in THF (10 mL) was added and themixture was stirred at ambient temperature overnight. Saturated NaHCO₃solution (50 mL) was added and the mixture was stirred for 15 minutes,then diluted with water (50 mL) and extracted with EtOAc (4×50 mL). Thecombined organics were washed with brine (2×60 mL), dried over anhydrousMgSO₄ and concentrated. The residue was purified by chromatography onsilica gel (hexanes/EtOAc/MeOH, 1:1:0.02) to give a mixture containingcompound 168 (6.29 g) as a light brown foam.

Synthesis of Compound 169

To a solution of the mixture containing compound 168 (6.29 g, 11.0 mmol)and DMAP (0.128 g, 1.05 mmol) in pyridine (40 mL) was added aceticanhydride (4.15 mL, 44.0 mmol). The mixture was stirred at ambienttemperature overnight, then diluted with EtOAc (100 mL), washed withsaturated NaHCO₃ solution (50 mL), water (50 mL) and brine (2×50 mL),dried over anhydrous MgSO₄ and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc, 1:3) to give compound 169(4.12 g, 81% from INT395) as a white foam.

Synthesis of Compound 170

A mixture of compound 169 (1.97 g, 4.28 mmol) and 80% acetic acid (15mL) was stirred at ambient temperature for 3 hours and thenconcentrated. The residue was purified by chromatography on silica gelto give compound 170 (1.35 g, 75%) as a yellow foam.

Synthesis of Compound 171

A mixture of compound 170 (1.29 g, 3.07 mmol) and NaIO₄ (1.32 g, 6.13mmol) in THF (20 mL) and water (10 mL) was stirred at ambienttemperature. After 1.5 hours, 0.20 g (0.92 mmol) more NaIO₄ was added.After 3 hours total reaction time the mixture was diluted with water (20mL) and extracted with CH₂Cl₂ (60 mL). The organic portion was washedwith brine (30 mL), dried over anhydrous MgSO₄ and concentrated to givecrude compound 171 that was used for the next reaction without furtherpurification.

Synthesis of Compound 172

To a solution of crude compound 171 (3.07 mmol) in THF (15 mL) and MeOH(5 mL) at 0° C. was added NaBH₄ (0.232 g, 6.14 mmol). The mixture wasstirred at 0° C. for 15 minutes then at ambient temperature for 1.5hours. The mixture was cooled to 0° C. and 80% acetic acid (10 mL) wasslowly added. The mixture was stirred at ambient temperature for 10minutes then diluted with EtOAc (80 mL) and washed with brine (2×30 mL).The organic portion was dried over anhydrous MgSO₄ and concentrated togive compound 172 (1.23 g, 95% from compound 170) as a light yellowfoam.

Synthesis of Compound 173

A mixture of compound 172 (1.23 g, 2.91 mmol), imidazole (0.600 g, 8.73mmol) and TBSCl (0.585 g, 3.76 mmol) in DMF (15 mL) was stirred atambient temperature for 35 minutes, then diluted with water (140 mL) andextracted with Et₂O (4×50 mL). The combined organics were washed withbrine (2×50 mL), dried over anhydrous MgSO₄ and concentrated. Theresidue was purified by chromatography on silica gel (hexanes;hexanes/EtOAc, 9:1, 4:1, 3:1) to give compound 173 (0.992 g, 64%) as awhite foam.

Synthesis of Compound 174

To a solution of compound 173 (0.990 g, 1.84 mmol) in pyridine (10 mL)was added methanesulfonyl chloride (0.257 mL, 3.32 mmol). The reactionmixture was stirred at ambient temperature for 1.5 hours, then dilutedwith EtOAc (50 mL), washed with water (20 mL) then brine (20 mL), driedover anhydrous MgSO₄ and concentrated to afford crude compound 174 (1.17g, white foam) that was used for the next reaction without furtherpurification.

Synthesis of Compound 175

A mixture of crude compound 174 (1.84 mmol) and NaN₃ (0.242 g, 3.68mmol) in dry DMF (15 mL) was stirred at 40° C. overnight. After coolingto ambient temperature, the mixture was diluted with water (150 mL) andextracted with Et₂O (4×50 mL). The combined organics were washed withbrine (2×50 mL), dried over anhydrous MgSO₄ and concentrated. Theresidue was purified by chromatography on silica gel (hexanes;hexanes/EtOAc, 9:1, 4:1) to give compound 175 (0.708 g, 69% fromcompound 173) as a white foam.

Synthesis of Compound 176

A mixture of compound 175 (0.397 g, 0.645 mmol), K₂CO₃ (0.446 g, 3.23mmol), water (5 mL) and MeOH (15 mL) was stirred at ambient temperaturefor 4 hours, then diluted with water (100 mL) and extracted with CH₂Cl₂(3×50 mL). The combined organics were washed with brine (2×50 mL), driedover anhydrous MgSO₄ and concentrated to afford compound 176 (0.284 g,92%) as a white solid that was used for the next reaction withoutfurther purification.

Synthesis of Compound 177

A mixture of compound 176 (0.284 g, 0.594 mmol), triphenylphosphine(0.472 g, 1.78 mmol), water (1 mL) and THF (15 mL) was stirred at 40° C.overnight and then concentrated. The residue was purified bychromatography on silica gel (CH₂Cl₂; CH₂Cl₂/MeOH, 19:1, 12:1;CH₂Cl₂/MeOH/Et₃N, 9:1:0.3) to give compound 177 (0.241 g, 90%) as awhite solid.

Synthesis of Compound 178

A mixture of compound 177 (0.234 g, 0.518 mmol) and 80% acetic acid (20mL) was stirred at ambient temperature overnight and then concentrated.The residue was dissolved in MeOH three times and concentrated.Precipitation from ACN/MeOH (20 mL) gave compound 178 (0.223 g,quantitative) as a white solid. LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 338.26; C₂₀H₃₆NO₃.

Example 18

Compounds 182-185, representative compounds of the invention, may beprepared according to the following Reaction Scheme 18. Any number ofcompounds related to compounds 182-185 could be produced using similarmethodology. Starting compound 95 may be prepared according to theprocedures describe above in Example 10.

In general, olefination using Me₂NCH₂CH₂PPh₃Br and KO^(t)Bu in THF givescompound 179. Lithium aluminum hydride reduction removes the acyl groupto give compound 180. Treatment with 80% acetic acid removes the cyclicketal group to give compound 181. Olefination using MePPh₃Br andKO^(t)Bu in THF gives compound 182. Treatment with 80% acetic acid formsthe salt compound 183.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 179

A mixture of KO^(t)Bu (101 mg, 0.9 mmol) and(2-dimethylaminoethyl)triphenylphosphonium bromide (373 mg, 0.9 mmol) inTHF (10 mL) was stirred at ambient temperature for 1 hour 20 min. Asolution of compound 95 (154 mg, 0.3 mmol) in THF (5 mL) was added andthe mixture was stirred at ambient temperature overnight. SaturatedNH₄Cl (1 mL) was added and the mixture was diluted with EtOAc (100 mL),washed with saturated NaHCO₃, brine, dried and concentrated. The crudeproduct was purified by column chromatography (EtOAc/MeOH, 9:1) to givecompound 179 (118 mg, 69%).

Synthesis of Compound 180

To a stirred solution of compound 179 (118 mg, 0.21 mmol) in THF (10.5mL) at 0° C. was added 1M LAH in THF (0.63 mL, 0.63 mmol) dropwise.After 30 min at 0° C., the mixture was stirred at ambient temperaturefor 3 hours. The mixture was cooled to 0° C. again and solidNa₂SO₄.10H₂O (203 mg, 0.63 mmol) was added portionwise. After 5 min at0° C., the mixture was stirred at ambient temperature for 45 min andthen filtered through Celite and washed with EtOAc. The filtrate wasconcentrated, and the crude compound 180 thus obtained was used in nextstep without purification.

Synthesis of Compound 181

A solution of crude compound 180 obtained above in 80% HOAc (5 mL) wasstirred at 40° C. for 7 hours 20 min. The solvents were removed byrotary evaporation and the residue was purified by column chromatography(EtOAc/MeOH/water/Et₃N, 7:2:0.5:0.5) to give compound 181 (73 mg, 96%from compound 179).

Synthesis of Compound 182

A mixture of Ph₃PMeBr (357 mg, 1.0 mmol) and KO^(t)Bu (112 mg, 1.0 mmol)in THF (5 mL) was stirred at ambient temperature for 1 hour 20 min. Asolution of compound 181 (73 mg, 0.2 mmol) in THF (3 mL) was added, andthe mixture was stirred at ambient temperature overnight. The reactionwas quenched with saturated NH₄Cl (0.5 mL) and the mixture was dilutedwith EtOAc (150 mL), washed with saturated NaHCO₃, brine, dried andconcentrated. The residue was purified by column chromatography(EtOAc/MeOH/water/Et₃N, 7:2:0.5:0.5, then EtOAc/MeOH/Et₃N, 7.5:2:0.5) toafford compound 182 (57 mg, 79%).

Synthesis of Compound 183

A solution of compound 182 (57 mg, 0.16 mmol) in 80% HOAc (1 mL) wasstirred at 40° C. for a few minutes and then the solvents were removedby rotary evaporation and the residue was dried under vacuum. Theproduct was dissolved in a small amount of MeOH and treated with a smallamount of ether. The salt precipitated out and dried under vacuum togive compound 183 (68 mg, quant.) as a pale powder. LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 362.09;C₂₃H₄₀NO₂.

Synthesis of Compound 184

Using the procedures described for the synthesis of compound 183, withthe exception of olefination by (4-chlorobenzyl)triphenyl-phosphoniumchloride, compound 184 (34 mg) was prepared in 51% yield starting fromcompound 95. Other notable exceptions were the use of HCl in MeOH toaffect the desilylation/deketalization step (to prepare the intermediateanalogous to compound 181) and the inclusion of the following doublebond hydrogenation step. The intermediate analogous to compound 181 wastreated with a catalytic amount of 10% Pd on carbon in THF and MeOHwhile under H₂ atmosphere. The catalyst was filtered off and thefiltrate was concentrated. The crude intermediate was treated with 80%HOAc to form the acetate salt of compound 184: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 434.68;C₂₆H₄₁ClNO₂.

Synthesis of Compound 185 Step 1: Synthesis of(3-pyridylmethyl)triphenylphosphonium chloride

To a stirred solution of 3-(chloromethyl)pyridine hydrochloride (5.17 g,31.5 mmol) in water (8 mL) was added K₂CO₃ (4.34 g, 31.5 mmol)portionwise. The resulting mixture was extracted three times withdiethyl ether. The extracts were combined and washed twice with brine,dried and concentrated. The residue (3.25 g, 25.5 mmol) was dissolved inxylene (30 mL) and Ph₃P (6.70 g, 25.5 mmol) was added. The mixture washeated at 133-134° C. overnight and then cooled to ambient temperature.The solid product was filtered, washed with toluene, and dried undervacuum to give (3-pyridylmethyl)triphenylphosphonium chloride (5.86 g,48%) as a pinkish solid.

Step 2: Synthesis of compound 185

Using the procedures described above for the synthesis of compound 184,with the exception of substitution by(3-pyridylmethyl)triphenylphosphonium chloride, compound 185 (19 mg) wasprepared in 20% yield starting from compound 95. LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 384.15; C₂₅H₃₈NO₂.

Example 19

Compound 189, a representative compound of the invention, may beprepared according to the following Reaction Scheme 19. Any number ofcompounds related to compound 189 could be produced using similarmethodology. Starting compound 93 may be prepared according to theprocedures described above in Example 10.

In general, catalytic hydrogenation of the double bond gives compound186. Lithium aluminum hydride reduction removes the acyl group to givecompound 187. Treatment with 80% acetic acid removes both the TBS groupand the cyclic ketal group to give compound 188. Olefination usingMePPh₃Br and KO^(t)Bu in THF gives compound 189.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 186

A mixture of compound 93 (98 mg, 0.19 mmol), 10% Pd/C (10 mg) in EtOH (4mL) was stirred under H₂ (1 atm) overnight. The catalyst was removed byfiltration and the filtrate was concentrated. The crude compound 186 (98mg) was used in next step without purification.

Synthesis of Compound 187

To a stirred solution of compound 186 (98 mg, 0.19 mmol) in THF (9 mL)at 0° C. was added 1M LAH in THF (0.86 mL, 0.86 mmol) dropwise. After 5min at 0° C., the mixture was stirred at ambient temperature for 6hours. The mixture was cooled to 0° C. again and solid Na₂SO₄.10H₂O (275mg, 0.86 mmol) was added portionwise. After 5 min at 0° C., the mixturewas stirred at ambient temperature for 1 hour and then filtered throughCelite. The filtrate was concentrated, and the crude product waspurified by column chromatography (hexanes/EtOAc, 1:1) to give compound187.

Synthesis of Compound 188

A solution of compound 187 obtained above in 80% HOAc (5 mL) was stirredat 40° C. for 7.5 hours. The solvents were removed by rotary evaporationand the residue was purified by column chromatography (EtOAc/hexanes,8:2 then 9:1) to give compound 188 (35 mg, 59% from compound 186).

Synthesis of Compound 189

A mixture of Ph₃PMeBr (196 mg, 0.55 mmol) and KO^(t)Bu (62 mg, 0.54mmol) in THF (5 mL) was stirred at ambient temperature for 1.5 hours. Asolution of compound 188 (35 mg, 0.11 mmol) in THF (2 mL) was added, andthe mixture was stirred at ambient temperature overnight. The reactionwas quenched with saturated NH₄Cl (1 mL) and the mixture was dilutedwith EtOAc (150 mL), washed with brine, dried and concentrated. Theresidue was purified by column chromatography (EtOAc/hexanes, 7:3) toyield compound 189 (37 mg, quant.). LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 324.74; C₂₀H₃₈NO₂.

Example 20

Compound 192, a representative compound of the invention, may beprepared according to the following Reaction Scheme 20. Any number ofcompounds related to compound 192 could be produced using similarmethodology.

In general, palladium catalyzed coupling of the olefin 93 with the arylhalide 4-BrC₆H₄OEt gives compound 190. Treatment with 80% acetic acidremoves the TBS group and the cyclic ketal to give compound 191.Olefination using MePPh₃Br and KO^(t)Bu in THF gives compound 192.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 190

A mixture of compound 93 (100 mg, 0.2 mmol), 4-bromophenetole (0.04 mL,0.28 mmol), tri(orthotolyl)phosphine (12 mg, 0.04 mmol), Pd(OAc)₂ (2.3mg, 0.01 mmol), Et₃N (0.06 mL) in acetonitrile (2 mL) was heated at 80°C. overnight. The solvents were removed and the residue was purified bycolumn chromatography (hexanes/EtOAc, 9:1 then 85:15) to yield compound190 (61 mg, 49%).

Synthesis of Compound 191

A solution of compound 190 in 80% HOAc (5 mL) was stirred at 40° C. for7.5 hours. The solvents were removed by rotary evaporation and theresidue was purified by column chromatography (EtOAc/hexanes, 8:2) togive compound 191 (27 mg, 60%).

Synthesis of Compound 192

A mixture of Ph₃PMeBr (114 mg, 0.32 mmol) and KO^(t)Bu (36 mg, 0.32mmol) in THF (3 mL) was stirred at ambient temperature for 1.5 hours. Asolution of compound 191 (27 mg, 0.064 mmol) in THF (1 mL) was added,and the mixture was stirred at ambient temperature overnight. Thereaction was quenched with saturated NH₄Cl (1 mL) and the mixture wasdiluted with EtOAc (150 mL), washed with brine, dried and concentrated.The residue was purified by column chromatography (EtOAc/hexanes, 1:1)to yield compound 192 (13 mg, 43%). LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 484.69; C₃₀H₄₆NO₄.

Example 21

Compounds 195-201, representative compounds of the invention, may beprepared according to the following Reaction Scheme 21. Any number ofcompounds related to compounds 195-201 could be produced using similarmethodology. Starting compound 85 may be prepared according toprocedures described above in Example 9.

In general, TPAP catalyzed oxidation of the free alcohol gives compound193. Olefination using (2-pyridylmethyl)triphenylphosphonium chlorideand KO^(t)Bu in THF gives compound 194. Lithium aluminum hydridereduction removes the acyl groups to give compound 195.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 193

To a solution of compound 85 (11.6 g, 28.4 mmol) in CH₂Cl₂ (100 mL) at0° C. were added TPAP (1.50 g, 4.26 mmol) and NMO (9.98 g, 85.2 mmol).The mixture was stirred at 0° C. for 10 minutes then at ambienttemperature for 3 hours. The mixture was concentrated to dryness and theresidue was purified by chromatography on silica gel (hexanes/EtOAc,3:2, 1:1; EtOAc) to give compound 193 (8.61 g, 75%) as a white solid.

Synthesis of Compound 194 Step 1: Synthesis of(2-pyridylmethyl)triphenylphosphonium chloride)

To a stirred solution of 2-(chloromethyl)pyridine hydrochloride (8.0 g,48.8 mmol) in water (20 mL) was added K₂CO₃ (6.74 g, 48.7 mmol)portionwise. The resulting mixture was extracted four times with diethylether. The extracts were combined and washed twice with brine, dried andconcentrated. The residue (5.78 g, 45.3 mmol) was dissolved in1,4-dioxane (19 mL) and Ph₃P (11.89 g, 45.3 mmol) was added. The mixturewas heated at 110° C. overnight and then cooled to ambient temperature.The solid product was filtered, washed with ether, and dried undervacuum to give (2-pyridylmethyl)triphenylphosphonium chloride (15.78 g,83%) as a pale solid.

Step 2: Synthesis of compound 194

A mixture of KO^(t)Bu (132 mg, 1.2 mmol) and(2-pyridylmethyl)triphenylphosphonium chloride (460 mg, 1.2 mmol) in THF(15 mL) was stirred at ambient temperature for 1.5 hours. A solution ofcompound 193 (195 mg, 0.48 mmol) in THF (5 mL) was added and the mixturewas stirred at ambient temperature overnight.

Saturated NH₄Cl (1 mL) was added and the mixture was diluted with EtOAc(150 mL), washed with brine, dried and concentrated. The crude productwas purified by column chromatography (EtOAc/hexanes, 1:1) to givecompound 194 (207 mg, 90%).

Synthesis of Compound 195

To a stirred solution of compound 194 (207 mg, 0.43 mmol) in THF (15 mL)at 0° C. was added 1M LAH in THF (1.9 mL, 1.9 mmol) dropwise. After 5min at 0° C., the mixture was stirred at ambient temperature for 6hours. The reaction was cooled to 0° C. again and solid Na₂SO₄.10H₂O(623 mg, 1.9 mmol) was added portionwise. After 5 min at 0° C., themixture was stirred at ambient temperature for 1 hour and then filteredthrough Celite and washed with EtOAc. The filtrate and washings werecombined and concentrated. The residue was purified by columnchromatography (EtOAc/MeOH, 95:5) to yield compound 195 (135 mg, 79%):LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 396.43; C₂₆H₃₈NO₂.

Synthesis of Compound 196

Using the procedures described for the synthesis of compound 195, withthe exception of olefination by (3-pyridylmethyl)triphenylphosphoniumchloride, compound 196 (90 mg) was prepared in 61% yield starting fromcompound 193: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 396.17; C₂₆H₃₈NO₂.

Synthesis of Compound 197

Using the procedures described for the synthesis of compound 195, withthe exception of olefination by hexyltriphenylphosphonium bromide,compound 197 (Z-isomer, 124 mg) was prepared in 85% yield starting fromcompound 193: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 405.86; C₂₆H₄₈NO₂.

Synthesis of compounds 198 and 201

Using the procedures described for the synthesis of compound 195, withthe exception of olefination by (3-benzyloxypropyl)triphenylphosphoniumbromide, compound 198 (Z-isomer, 114 mg, 68%) and compound 201, productof debenzylation, (Z-isomer, 10 mg, 7%) were prepared starting fromcompound 193. Compound 198: LC/MS (direct infusion, electrospray +ve, 10mM NH₄OAc in 3:7 water and MeCN) 452.57; C₃₀H₄₄O₃. Compound 201: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)363.15; C₂₃H₃₉O₃.

Synthesis of Compound 199

Using the procedures described for the synthesis of compound 195, withthe exceptions of olefination by(2-dimethylaminoethyl)triphenylphosphonium bromide, and salt formationwith acetic acid, compound 199 (Z-isomer, 93 mg) was prepared in 57%yield starting from compound 193: LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 376.06; C₂₄H₄₂NO₂.

Synthesis of Compound 200

Using the procedures described for the synthesis of compound 195, withthe exceptions of olefination by (4-chlorobenzyl)triphenylphosphoniumchloride, compound 200 (118 mg) was prepared in 74% yield starting fromcompound 193.

Example 22

Compound 203, a representative compound of the invention, may beprepared according to the following Reaction Scheme 22. Any number ofcompounds related to compound 203 could be produced using similarmethodology. Starting compound 193 may be prepared according toprocedures described above in Example

In general, olefination using methyl(triphenylphosphoranylidene)acetatein THF gives compound 202. Lithium aluminum hydride reduces the estergroups to give compound 203.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 202

A mixture of compound 193 (300 mg, 0.74 mmol) and methyl(triphenylphosphoranylidene)acetate (742 mg, 2.2 mmol) in THF (30 mL)was stirred at 67° C. overnight and then at 80° C. for one day. Thesolvent was removed and the residue was purified by columnchromatography (hexanes/EtOAc, 8:2) to give compound 202 (328 mg, 96%).

Synthesis of Compound 203

To a stirred solution of compound 202 (179 mg, 0.39 mmol) in THF (15 mL)at 0° C. was added 1 M LAH in THF (2.2 mL, 2.2 mmol) dropwise. After 5min at 0° C., the mixture was stirred at ambient temperature for 6 hours10 min. The reaction was cooled to 0° C. again and solid Na₂SO₄.10H₂O(715 mg, 2.2 mmol) was added portionwise. After 5 min at 0° C., themixture was stirred at ambient temperature for 1 hour and then filteredthrough Celite and washed with EtOAc. The filtrate and washings werecombined and concentrated. The residue was purified by columnchromatography (EtOAc/MeOH, 95:5) to yield compound 203 (66 mg, 49%):LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 331.06; C₂₂H₃₅O₂.

Example 23

Compounds 210-212 may be prepared according to the following ReactionScheme 23. Any number of compounds related to compounds 210-212 could beproduced using similar methodology. Starting compound 90 may be preparedaccording to procedures described above in Example 10.

In general, TPAP catalyzed oxidation of the free alcohol gives compound205. Olefination using (4-chlorobenzyl)triphenylphosphonium chloride andKO^(t)Bu in THF gives compound 206 and the E-isomer compound 207.Lithium aluminum hydride reduction removes the acyl group to givecompound 208. Treatment with 80% acetic acid removes the TBS group andthe cyclic ketal group to give compound 209. Olefination using MePPh₃Brand KO^(t)Bu in THF gives compound 210.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 205

To a solution of compound 204 (8.60 g, 16.4 mmol) in CH₂Cl₂ (100 mL) at0° C. were added TPAP (0.86 g, 2.5 mmol) and NMO (5.76 g, 49.2 mmol).The mixture was stirred at 0° C. for 5 minutes then at ambienttemperature. After 3 hours, more TPAP (0.29 g, 0.83 mmol) and NMO (1.92g, 16.4 mmol) were added and stirring continued. After 5.5 hours totalreaction time the mixture was concentrated to dryness. The residue waspurified by chromatography on silica gel (hexanes/EtOAc, 49:1, 19:1,9:1, 4:1) to give compound 205 (5.13 g, 60%) as a white solid.

Synthesis of compounds 206 and 207

A mixture of KO^(t)Bu (0.136, 1.15 mmol) and(4-chlorobenzyl)triphenylphosphonium chloride (0.496 g, 1.15 mmol) inTHF (10 mL) was stirred at ambient temperature for 1 hour, then asolution of compound 205 (0.20 g, 0.38 mmol) in THF (5 mL) was added.The reaction mixture was stirred at ambient temperature overnight, thenquenched with saturated NH₄Cl solution (1 mL), diluted with EtOAc (150mL), washed with brine (2×25 mL), dried over anhydrous MgSO₄ andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc) to give compound 206 (0.093, 39%) as a colourless glassand compound 207 (0.126 g, 53%) as a colourless glass.

Synthesis of Compound 208

To a solution of compound 206 (0.15 mmol) in THF (10 mL) was addedLiAlH₄ (0.59 mL of a 1 M solution in THF, 0.59 mmol). The mixture wasstirred at ambient temperature overnight, then quenched withNa₂SO₄.10H₂O and stirred for 30 minutes. The mixture was filtered,rinsing with EtOAc, and concentrated to dryness to give crude compound208 (0.089 g, colourless glass) that was used in the next reactionwithout further purification.

Synthesis of Compound 209

Crude compound 208 (0.15 mmol) was dissolved in 80% acetic acid (10 mL)with THF (1 mL) and MeOH (1 mL) and stirred at 40° C. for 4.5 hours,then at ambient temperature overnight. The mixture was concentrated togive crude compound 209 (0.074 g) as a colourless glass that was used inthe next reaction without further purification.

Synthesis of Compound 210

A mixture of KO^(t)Bu (0.122, 1.03 mmol) and MePPh₃Br (0.368 g, 1.03mmol) in THF (5 mL) was stirred at ambient temperature for 1 hour, thena solution of compound 209 (0.074 g, 0.17 mmol) in THF (5 mL) was added.The reaction mixture was stirred at ambient temperature overnight, thenquenched with saturated NH₄Cl solution (1 mL), diluted with EtOAc (100mL), washed with brine (2×20 mL), dried over anhydrous MgSO₄ andconcentrated. The residue was purified by chromatography on silica gel(hexanes/EtOAc, 3:1, 1:1) to afford compound 210 (0.035 g, 21% fromcompound 205) as a white solid after concentration from CH₂Cl₂. LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)411.14; C₂₇H₃₆ClO.

Synthesis of Compound 211

Using the procedure described for the synthesis of compound 208,compound 207 (0.126 g, 0.200 mmol) was reacted with LiAlH₄ (0.80 mL of a1 M solution in THF, 0.80 mmol) to give the alcohol intermediate (0.121g, colourless glass).

Using the procedure described for the synthesis of compound 209, thealcohol intermediate (0.20 mmol) was converted to ketone intermediate(0.104 g, colourless glass). Using the procedure described for thesynthesis of compound 210, with the exception that a different solventsystem was used for chromatography on silica gel (hexanes/EtOAc, 4:1,7:3, 3:2, 1:1), the ketone intermediate (0.20 mmol) was converted to thealkene. Concentration from CH₂Cl₂ gave compound 211 (0.058 g, 36% fromcompound 205) as a light yellow solid: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 411.09; C₂₇H₃₆ClO.

Synthesis of Compound 212

Using the procedure described for the synthesis of compound 206, withthe exception that a different solvent system was used forchromatography on silica gel (EtOAc/MeOH, 9:1; EtOAc/MeOH/Et₃N,9:0.75:0.25), compound 205 (0.20 g, 0.38 mmol) was reacted with(2-dimethylaminoethyl)triphenylphosphonium bromide (0.485 g, 1.15 mmol)to give the amine intermediate (0.204 g, 93%, yellow oil). Using theprocedure described for the synthesis of compound 208, with theexceptions that 0.76 mL more LiAlH₄ solution (1 M in THF, 0.76 mmol)were added after 2.5 hours and total reaction time was 5.5 hours, theamine intermediate (0.35 mmol) was reacted with LiAlH₄ (0.76 mL of a 1 Msolution in THF, 0.76 mmol) to give the alcohol intermediate (0.203 g,colourless glass). Using the procedure described for the synthesis ofcompound 209, with the exceptions that THF and MeOH were not added andthe reaction mixture was not heated, the alcohol intermediate (0.35mmol) was converted to ketone intermediate as the acetic acid salt(0.189 g, colourless glass). Using the procedure described for thesynthesis of compound 210, with the exceptions that 0.331 g (2.80 mmol)KO^(t)Bu, 1.00 g (2.80 mmol) MePPh₃Br and 15 mL THF were used, and afterquenching the reaction mixture was concentrated, then purified bychromatography on silica gel (EtOAc/MeOH, 9:1; EtOAc/MeOH/Et₃N,9:0.9:0.1, 9:0.75:0.25), the ketone intermediate (0.35 mmol) wasconverted to the alkene. A mixture of the alkene, 80% AcOH (1 mL) andMeOH (5 mL) was concentrated by rotary evaporation. Precipitation fromEt₂O afforded compound 212 (0.072 g, 43% from compound 205) as a whitesolid: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7water and MeCN) 375.98; C₂₄H₄₂NO₂.

Example 24

Compounds 219-222, representative compounds of the invention, may beprepared according to the following Reaction Scheme 24. Any number ofcompounds related to compounds 219-222 could be produced using similarmethodology. Starting compound 35 may be prepared according toprocedures described above in Example 3.

In general, reaction with acetic anhydride and DMAP in pyridine givescompound 213. Treatment with HCl and water in THF removes the cyclicketal group to give compound 214. Olefination using MePPh₃Br andKO^(t)Bu in THF gives compound 215. Tetrabutylammonium fluoride removesthe tert-butyldiphenylsilyl group to give compound 216. TPAP catalyzedoxidation of the free alcohol gives compound 217.

Olefination using (2-dimethylaminoethyl)triphenylphosphonium bromide andKO^(t)Bu in THF gives compound 218. Lithium aluminum hydride reductionremoves the acyl groups to give compound 219. Treatment with 80% aceticacid forms the salt compound 220.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 213

To a solution of compound 35 (67 mmol) in pyridine (150 mL) at 0° C.were added DMAP (1.0 g, 8.2 mmol) and acetic anhydride (12.7 mL, 134mmol). The reaction mixture was stirred at ambient temperature for 2hours. The reaction was quenched with water and diluted with EtOAc, thenconcentrated to dryness to give crude compound 213 that was used for thenext reaction without further purification.

Synthesis of Compound 214

A mixture of compound 213 (67 mmol), HCl (20 mL), water (50 mL) and THF(150 mL) was stirred at 60-65° C. for 2 hours, then cooled to ambienttemperature.

With K₂CO₃ the mixture was adjusted to pH=7.0-8.0, then water and CH₂Cl₂were added. The mixture was dried over anhydrous MgSO₄ and concentrated.Precipitation from EtOAc gave a crude mixture that contained compound214 (white solid) and was used in the next reaction without furtherpurification.

Synthesis of Compound 215

A mixture of KO^(t)Bu (9.43 g, 83.9 mmol) and MePPh₃Br (30.0 g, 83.9mmol) in THF (200 mL) was stirred at ambient temperature, then crudecompound 214 (67 mmol) was added and the mixture was stirred at ambienttemperature for 2 hours.

The reaction was quenched with cold water and extracted with EtOAc. Theorganic portion was concentrated to dryness, then the residue wastreated with hexanes/EtOAc (4:1), filtered and the filtrate wasconcentrated to dryness. The residue was dissolved in pyridine andacetic anhydride was added. The mixture was stirred at ambienttemperature for 2 hours, then quenched with water and extracted withEtOAc. The organic portion was concentrated to dryness to give crudecompound 215 that was used in the next reaction without furtherpurification.

Synthesis of Compound 216

A mixture of crude compound 215 (67 mmol) and TBAF (30 mL of a 1 Msolution in THF, 30 mmol) in THF (80 mL) was stirred at ambienttemperature for 2 hours then at 70° C. for 1 hour. The mixture wasconcentrated and the residue was purified by chromatography on silicagel to give compound 216 (6.12 g, 22% from compound 35) as a whitesolid.

Synthesis of Compound 217

To a solution of compound 216 (6.0 g, 15 mmol) in CH₂Cl₂ (50 mL) wereadded TPAP (0.052 g, 0.15 mmol) and NMO (4.4 g, 38 mmol). The mixturewas stirred at ambient temperature. After 2 hours, more TPAP (0.052 g,0.15 mmol) was added and stirring continued. After 3 hours totalreaction time, the mixture was concentrated.

The residue was purified by chromatography on silica gel (hexanes/EtOAc,9:1) to give compound 217 (2.9 g, 48%) as a white solid.

Synthesis of Compound 218

A mixture of KO^(t)Bu (0.157, 1.33 mmol) and(2-dimethylaminoethyl)triphenylphosphonium bromide (0.563 g, 1.33 mmol)in THF (10 mL) was stirred at ambient temperature for 1 hour, then asolution of compound 217 (0.20 g, 0.49 mmol) in THF (5 mL) was added.The reaction mixture was stirred at ambient temperature overnight, thenquenched with saturated NH₄Cl solution (1 mL), diluted with EtOAc (150mL), washed with brine (2×25 mL), dried over anhydrous MgSO₄ andconcentrated. The residue was purified by chromatography on silica gel(EtOAc/MeOH, 9:1; EtOAc/MeOH/Et₃N, 9:0.75:0.25) to give compound 218(0.197, 88%) as a white foam.

Synthesis of Compound 219

To a solution of compound 218 (0.197 g, 0.428 mmol) in THF (10 mL) wasadded LiAlH₄ (0.98 mL of a 1 M solution in THF, 0.98 mmol). The mixturewas stirred at ambient temperature for 4 hours, then quenched withNa₂SO₄.10H₂O and stirred for 30 minutes. The mixture was filtered,rinsing with EtOAc, and concentrated to dryness. The residue waspurified by chromatography on silica gel (EtOAc/MeOH, 9:1;EtOAc/MeOH/Et₃N, 9:0.75:0.25, 9:0.5:0.5) to give compound 219 as a whitesolid that was used for the next reaction.

Synthesis of Compound 220

A mixture of compound 219, 80% AcOH (1 mL) and MeOH (5 mL) wasconcentrated by rotary evaporation. Concentration from CH₂Cl₂ affordedcompound 220 (0.154 g, 72% from compound 217) as a white foam: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)375.96; C₂₄H₄₂NO₂.

Synthesis of compounds 221 and 222

Using the procedure described for the synthesis of compound 218, withthe exception that a different solvent system was used forchromatography on silica gel (hexanes/EtOAc, 3:1, 3:2), compound 217(0.20 g, 0.49 mmol) was reacted with(3-pyridylmethyl)triphenylphosphonium chloride (0.519 g, 1.33 mmol) togive a mixture of alkene intermediates (0.195 g, colourless glass).Using the procedure described for the synthesis of compound 219, withthe exceptions that reaction time was 3 hours and different solventsystems were used for chromatography on silica gel (EtOAc/MeOH andCH₂Cl₂/acetone), the alkene intermediate mixture (0.41 mmol) was reactedwith LiAlH₄ (0.81 mL of a 1 M solution in THF, 0.81 mmol) to givecompound 221 (Z-isomer) (0.037 g, 19% from compound 217) as a white foamafter concentration from CH₂Cl₂ and compound 222 (E-isomer) (0.047 g,24% from compound 217) as a white solid after precipitation from Et₂O.Compound 221: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 395.98; C₂₆H₃₈NO₂. Compound 222: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 395.96;C₂₆H₃₈NO₂.

Example 25

Compound 225, a representative compound of the invention, may beprepared according to the following Reaction Scheme 25. Any number ofcompounds related to compound 225 could be produced using similarmethodology. Starting compound 76 may be prepared according toprocedures described above in Reaction Scheme 8.

In general, reaction of compound 76 with triphenylphosphine and water inTHF reduces the azide group to give compound 223. The amine group isconverted to the sulfonamide compound 224 using MsCl and triethylaminein CH₂Cl₂. Treatment with potassium carbonate in methanol and watergives compound 225.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 223

A solution of compound 76 (6.00 g, 13.9 mmol), PPh₃ (5.85 g, 22.3 mmol),water (3.72 mL, 206 mmol) and THF (100 mL) was heated overnight at 40°C. The reaction mixture was concentrated and the residue was purified bychromatography on silica gel (EtOAc/MeOH/Et₃N 90:10 then 90:10:3) toafford compound 223 (4.59 g, 81%) as a white foam.

Synthesis of Compound 224

A solution of compound 223 (250 mg, 0.616 mmol), MsCl (72 μL, 0.92mmol), Et₃N (258 μL, 1.84 mmol) and CH₂Cl₂ was stirred at ambienttemperature under argon for 1.5 hours. The reaction was quenched withsaturated NaHCO₃ solution (3 mL) and water (2 mL). The solution wasfurther diluted with water (5 mL) and was extracted with 100 mL ofEtOAc. The EtOAc solution was washed with water and brine, then driedover MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (hexanes/EtOAc 3:1, then 1:1) to affordcompound 224 (310 mg, quantitative) as a white foam.

Synthesis of Compound 225

A solution of compound 224 (223 mg, 0.46 mmol), K₂CO₃ (255 mg, 1.84mmol), water (3 mL) and methanol (6 mL) was heated at reflux for 2hours. The reaction mixture was concentrated, then dissolved in waterand CH₂Cl₂ and was extracted with CH₂Cl₂ (240 mL). The CH₂Cl₂ solutionwas washed with water and brine, then dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(CH₂Cl₂/MeOH 100:0, then 19:1, then 9:1). The residue from the purefractions was concentrated from a minimum of MeOH and acetonitrile (5mL) to afford compound 225 (132 mg, 72%) as a white powder: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)381.90; C₂₁H₃₅NO₃S, 363.85; C₂₁H₃₃NO₂S.

Example 26

Compound 227, a representative compound of the invention, may beprepared according to the following Reaction Scheme 26. Any number ofcompounds related to compound 227 could be produced using similarmethodology. Starting compound 77 may be prepared according toprocedures described above in Example 8.

In general, reaction of compound 77 with acetic anhydride and DMAP inpyridine acylates the hydroxyl and amino groups to give compound 226.Selective lithium aluminum hydride reduction of the acetates givescompound 227.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 226

A solution of compound 77 (208 mg, 0.647 mmol), acetic anhydride (214μL, 2.27 mmol), DMAP (17 mg) and pyridine (5 mL) was stirred overnightat ambient temperature. The reaction was quenched with brine and wasextracted with EtOAc.

The EtOAc solution was washed with brine, then dried over MgSO₄,filtered and concentrated. The residual solvent was removed bycodistillation with toluene. The residue was purified by chromatographyon silica gel (EtOAc) to afford compound 226 (235 mg, 81%).

Synthesis of Compound 227

A solution of LiAlH₄ (1.57 mL of a 1.0 M solution in THF) was added toan ice cooled solution of compound 226 (235 mg, 0.525 mmol) in THF (10mL). After 10 minutes the solution was continued at ambient temperaturefor another 2 hours. The reaction was quenched with Na₂SO₄.10H₂O. After1 hour MgSO₄ was added and the solution was filtered and concentrated.The resulting crystalline solid was triturated successively with Et₂O,CH₂Cl₂, EtOAc and MeOH to afford compound 227 (128 mg, 67%) as a whitepowder. LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7water and MeCN) 386.48; C₂₂H₃₇NNaO₃.

Example 27

Compounds 229 and 231-233, representative compounds of the invention,may be prepared according to the following Reaction Scheme 27. Anynumber of compounds related to compounds 229 and 231-233 could beproduced using similar methodology. Starting compound 223 may beprepared according to procedures described above in Example 25.

In general, reaction of an amino compound such as compound 223 withbenzoyl chloride gives the amide compound 230. Lithium aluminum hydridereduces the amide and the acetates to give compound 231. Treatment with80% acetic acid forms the salt compound 232.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 230

A solution of compound 223 (405 mg, 1.00 mmol), benzoyl chloride (0.17mL, 1.46 mmol), DMAP (15 mg), pyridine (4 mL) and CH₂Cl₂ (6 mL) wasstirred for 2 hours at ambient temperature. The reaction was dilutedwith EtOAc (250 mL) and was washed with saturated NaHCO₃ solution andbrine, then dried over NaSO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel (EtOAc/hexanes 45:55) to affordcompound 230 (490 mg, 96%) as a colourless syrup.

Synthesis of Compound 231

A solution of LiAlH₄ (6×4.8 mL of a 1.0 M solution in THF) was addedover 3 days to a solution of compound 230 (490 mg, 0.96 mmol) in THF (20mL) at reflux under argon. The reaction was cooled in ice and wasquenched with Na₂SO₄.10H₂O. After 20 minutes the solution was filteredand concentrated. The residue was purified by chromatography (EtOAc/MeOH95:5) to afford compound 231 (395 mg, 39%) as a crystalline solid.

Synthesis of Compound 232

A solution of compound 231 (150 mg, 0.36 mmol) and 80% AcOH was heatedat 40° C. for 10 minutes. The solution was concentrated to give compound232 (162 mg, 94%) as a white foam. LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 412.16; C₂₇H₄₂NO₂.

Synthesis of Compound 233

Using the procedures described for the synthesis of compound 232, withthe exception of substitution by cyclopropane carbonyl chloride,compound 233 (231 mg) was prepared as a white solid in 67% yieldstarting from compound 223: LC/MS (direct infusion, electrospray +ve, 10mM NH₄OAc in 3:7 water and MeCN) 376.35; C₂₄H₄₂NO₂.

Synthesis of Compound 229

Using the procedures described for the synthesis of compound 232,compound 229 (549 mg) was prepared as a glass-like solid in 36% yieldstarting from compound 226. LC/MS (direct infusion, electrospray +ve, 10mM NH₄OAc in 3:7 water and MeCN) 350.63; C₂₂H₄₀NO₂.

Example 28

Compounds 235-236, representative compounds of the invention, may beprepared according to the following Reaction Scheme 28. Any number ofcompounds related to compounds 235-236 could be produced using similarmethodology. Starting compound 223 may be prepared according toprocedures described above in Example 25.

In general, reaction of an amino compound such as compound 223 with analdehyde such as formaldehyde and a reducing agent such as NaBH₃CN givesa tertiary amino compound such as compound 234. A reducing agent such aslithium aluminum hydride is used to reduce the ester-protected hydroxylsto give compound 235. Treatment with 80% acetic acid forms the ammoniumacetate salt compound 236.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 234

NaBH₃CN (2×25 mg, 0.8 mmol) was added over 25 minutes to a ambienttemperature solution of compound 223 (99 mg, 0.24 mmol), 37% CH₂O inwater (0.1 mL) and acetonitrile (2 mL). After 15 minutes the pH of thesolution was adjusted to pH by the dropwise addition of 80% acetic acid.After 1 hour the reaction mixture was diluted with EtOAc (150 mL) andwas washed with saturated NaHCO₃ solution and brine, then dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (EtOAc/MeOH 95:5) to afford compound 234(104 mg, 98%).

Synthesis of Compound 235

A solution of LiAlH₄ (5.5 mL of a 1.0 M solution in THF) was added to anice cooled solution of compound 234 (492 mg, 1.1 mmol) in THF (15 mL)under argon.

After 25 minutes the cold bath was removed and the reaction wascontinued for 4 hours at ambient temperature. The reaction was cooled inice and was quenched with Na₂SO₄.10H₂O. After 10 minutes at ambienttemperature, the solution was filtered, rinsing with EtOAc and thefiltrate was washed with brine, then dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gel(EtOAc/MeOH/H₂O 16:3:1) to afford compound 235 (294 mg, 74%) as acrystalline solid.

Synthesis of Compound 236

A solution of compound 235 (287 mg, 0.82 mmol) and 80% AcOH (10 mL) wasstirred at 40° C. for 10 minutes, then concentrated. Repeatedconcentration from a minimum of methanol in acetonitrile gave compound236 (287 mg, 85%) as a white solid: LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 350.69; C₂₂H₄₀NO₂.

Example 29

Compounds 240-241, representative compounds of the invention, may beprepared according to the following Reaction Scheme 29. Any number ofcompounds related to compounds 240-241 could be produced using similarmethodology. Starting compound 223 may be prepared according toprocedures described above in Example 25.

In general, an amino compound may be converted to a sulfonamide such asthe reaction of compound 223 with a sulfonyl chloride such as2-nitrobenzenesulfonyl chloride to give compound 237. The sulfonamidenitrogen in a compound such as 237 may then be alkylated with anelectrophile such as methyl iodide to give an amine compound such as238. The sulfonamide may be cleaved by reaction with a nucleophile suchas the thiophenolate anion to give compound 239. The acetates may beremoved by base hydrolysis to give compound 240. Treatment with 80%acetic acid forms the ammonium acetate salt compound 241.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 237

2-Nitrobenzenesulfonyl chloride (194 mg, 0.88 mmol) was added to an icecooled solution of compound 223 (296 mg, 0.73 mmol), Et₃N (180 μL, 1.3mmol) and CH₂Cl₂ (5 mL) under argon. After 30 minutes the cold bath wasremoved and the reaction was continued for 1 hour at ambienttemperature. The reaction mixture was diluted with EtOAc and was washedwith saturate NaHCO₃ solution and brine, then dried over MgSO₄, filteredand concentrated to afford compound 237 (433 mg, 100%) as a pale yellowsolid.

Synthesis of Compound 238

MeI (60 L and 2×30 L, 1.9 mmol) was added over 7 hours to a solution ofcompound 237 (431 mg, 0.73 mmol), K₂CO₃ (232 mg, 1.7 mmol) and DMF (3mL) under argon. After stirring overnight at ambient temperature, thereaction mixture was diluted with EtOAc and was washed with brine, thendried over MgSO₄, filtered and concentrated to give crude compound 238that was used in the next step without further purification.

Synthesis of Compound 239

A solution of compound 238 (crude, 0.73 mmol), PhSH (225 μL, 2.19 mmol),CsCO₃ (714 mg, 2.19 mmol) and acetonitrile (6 mL) was heated at 55° C.under argon for 1.5 hours. The ambient temperature reaction mixture wasdiluted with EtOAc and was washed with brine, then dried with MgSO₄,filtered and concentrated.

The residue was purified by chromatography on silica gel (EtOAc/hexanes1:1, then EtOAc/MeOH/Et₃N 90:10:2) to afford compound 239 (268 mg, 88%)as a pale yellow oil.

Synthesis of Compound 240

A solution of compound 239 (268 mg, 0.639 mmol), 10% KOH in water (1 mL)and MeOH (5 mL) was heated at 55° C. for 4 hours. The ambienttemperature reaction mixture was diluted with EtOAc (80 mL) and waswashed with brine, then dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel(EtOAc/MeOH/H₂O/NH₄OH 80:15:5:1.5, then 70:20:10:2) to afford compound240 (182 mg, 85%) as a white foam.

Synthesis of Compound 241

A solution of compound 240 (182 mg, 0.542 mmol) and 80% AcOH was heatedat 40° C. for 15 minutes, then concentrated. Residual solvent wasremoved by codistillation with methanol to afford compound 241 (210 mg,98%) as a pale yellow foam. LC/MS (direct infusion, electrospray +ve, 10mM NH₄OAc in 3:7 water and MeCN) 336.08; C₂₁H₃₈NO₂.

Example 30

Compound 242, a representative compound of the invention, may beprepared according to the following Reaction Scheme 30. Any number ofcompounds related to compound 242 could be produced using similarmethodology. Starting compound 77 may be prepared according toprocedures described above in Example 8.

In general, reaction of an amino compound such as 77 withpyrazole-1-carboxamidine hydrochloride and diisopropylethylamine (DIEA)in methanol gives compound 242.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 242

A solution of compound 77 (106 mg, 0.33 mmol), pyrazole-1-carboxamidinehydrochloride (51 mg, 0.35 mmol), DIEA (61 μl, 0.35 mmol) and MeOH (165μl) was stirred at ambient temperature under argon for 3 days. Theslurry was triturated in Et₂O, decanting off the solvent to give a whitepowder. The solid was then recrystallized from 3 ml of EtOAc/MeOH/Et₂Oto afford compound 242 (64 mg, 48%) as a white solid: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 364.06;C₂₁H₃₈N₃O₂.

Example 31

Compounds 243-250, representative compounds of the invention, may beprepared according to the following Reaction Scheme 31. Any number ofcompounds related to compounds 243-250 could be produced using similarmethodology. Starting compound 77 may be prepared according toprocedures described above in Example 8.

In general, reductive amination of an amino compound such as compound 77with a ketone or aldehyde such as isobutyraldehyde gives an amine suchas compound 243. Treatment with 80% acetic acid gives the salt compound244.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 243

To a stirred mixture of compound 77 (100 mg, 0.31 mmol) in1,2-dichloroethane (5 mL) and EtOH (1 mL) were added isobutyraldehyde(0.14 mL, 1.5 mmol), 4 Å molecular sieves (100 mg), and NaB(OAc)₃H (197mg, 0.93 mmol). The mixture was stirred at ambient temperature for threedays and then filtered through Celite and washed with EtOAc. Thefiltrate and washings were combined and concentrated. The residue waspurified by column chromatography (EtOAc/MeOH, 9:1 then 8:2) to yieldcompound 243 (79 mg, 67%).

Synthesis of Compound 244

A solution of compound 243 (79 mg) in 80% HOAc (2 mL) was stirred at 40°C. for a few minutes and then concentrated by rotary evaporation. Theresidue was codistilled with MeOH several times and dried under vacuum.The product was dissolved in a small amount of MeOH and treated with asmall amount of acetonitrile. The solvents were removed and the productwas dried under vacuum to give compound 244 (91 mg, 99%): LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 378.21;C₂₄H₄₄NO₂.

Synthesis of Compound 245

Using the procedures described for the synthesis of compound 244, withthe exception of substitution by 1-methyl-4-piperidone, compound 245(183 mg) was prepared in quantitative yield starting from compound 77:LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 419.21; C₂₆H₄₇N₂O₂.

Synthesis of Compound 246

Using the procedures described for the synthesis of compound 244, withthe exception of substitution by 3-nitrobenzaldehyde, compound 246 (58mg) was prepared in 35% yield starting from compound 77: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 457.22;C₂₇H₄₁N₂O₄.

Synthesis of Compound 247

Using the procedures described for the synthesis of compound 244, withthe exception of substitution by piperonal, compound 247 (161 mg) wasprepared in 99% yield starting from compound 77: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 456.12; C₂₈H₄₂NO₄.

Synthesis of Compound 248

Using the procedures described for the synthesis of compound 244, withthe exception of substitution by pyrrole-2-carboxaldehyde, compound 248(131 mg) was prepared in 91% yield starting from compound 77: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)401.15; C₂₅H₄₁N₂O₂.

Synthesis of Compound 249

Using the procedures described for the synthesis of compound 244, withthe exception of substitution by 2-furaldehyde, compound 249 (88 mg) wasprepared in 61% yield starting from compound 77: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 402.23; C₂₅H₄₀NO₃.

Synthesis of Compound 250

Using the procedures described for the synthesis of compound 244, withthe exception of substitution by 3-pyridinecarboxaldehyde, compound 250(59 mg) was prepared in 40% yield starting from compound 77: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)413.22; C₂₆H₄₁N₂O₂.

Example 32

Compounds 252-261, representative compounds of the invention, may beprepared according to the following Reaction Scheme 32. Any number ofcompounds related to compounds 252-261 could be produced using similarmethodology. Starting compound 193 may be prepared according toprocedures described above in Example 9.

In general, reductive amination of a ketone or aldehyde compound such ascompound 193 with an amine such as pyrrolidine gives an amine such ascompound 251. Lithium aluminum hydride reduction removes the acyl groupsto give compound 252. Treatment with 80% acetic acid gives the saltcompound 253.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 251

To a stirred solution of compound 193 (150 mg, 0.37 mmol) in1,2-dichloroethane (7.5 mL) were added pyrrolidine (0.18 mL, 2.2 mmol),4 Å molecular sieves (150 mg), and NaB(OAc)₃H (314 mg, 1.5 mmol). Themixture was stirred at ambient temperature for three days and thenfiltered through Celite and washed with EtOAc. The filtrate and washingswere combined and concentrated. The residue was purified by columnchromatography (EtOAc/MeOH/Et₃N, 8:2:0.5) to yield compound 251 (155 mg,91%).

Synthesis of Compound 252

To a stirred solution of compound 251 (155 mg, 0.34 mmol) in THF (15 mL)at 0° C. was added 1M LAH in THF (1.7 mL, 1.7 mmol) dropwise. After 5min at 0° C., the mixture was stirred at ambient temperature for 5 hours40 min. The reaction was cooled to 0° C. again and solid Na₂SO₄.10H₂O(536 mg, 1.7 mmol) was added portionwise. After 5 min at 0° C., themixture was stirred at ambient temperature for 1 hour and then filteredthrough Celite and washed with EtOAc. The filtrate and washings werecombined and concentrated. The residue was purified by columnchromatography (EtOAc/MeOH/water/Et₃N, 8:1:0.5:0.5) to yield compound252 (121 mg, 92%).

Synthesis of Compound 253

A solution of compound 252 (121 mg) in 80% HOAc (2 mL) was stirred at40° C. for a few minutes and then concentrated by rotary evaporation.The residue was codistilled with MeOH several times and dried undervacuum. The product was dissolved in a small amount of MeOH and treatedwith a small amount of acetonitrile.

The solvents were removed and the product was dried under vacuum to givecompound 253 (147 mg, quant.): LC/MS (direct infusion, electrospray +ve,10 mM NH₄OAc in 3:7 water and MeCN) 376.24; C₂₄H₄₂NO₂.

Synthesis of Compound 254

Using the procedures described for the synthesis of compound 253, withthe exception of substitution by ethanolamine, compound 254 (84 mg) wasprepared in 51% yield starting from compound 193: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 366.13;C₂₂H₄₀NO₃.

Synthesis of Compound 255

Using the procedures described for the synthesis of compound 253, withthe exception of substitution by N,N-dimethylethylenediamine, compound255 (38 mg) was prepared in 20% yield starting from compound 193: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)393.11; C₂₆H₄₉N₂O₄.

Synthesis of Compound 256

Using the procedures described for the synthesis of compound 253, withthe exception of substitution by cyclohexylamine, compound 256 (154 mg)was prepared in 87% yield starting from compound 193: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 404.28;C₂₆H₄₆NO₂.

Synthesis of Compound 257

Using the procedures described for the synthesis of compound 253, withthe exception of substitution by 3-(aminomethyl)pyridine, compound 257(122 mg) was prepared in 65% yield starting from compound 193: LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)413.15; C₂₆H₄₁N₂O₂.

Synthesis of Compound 258

Using the procedures described for the synthesis of compound 253, withthe exception of substitution by furfurylamine, compound 258 (83 mg) wasprepared in 47% yield starting from compound 193: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 402.20;C₂₅H₄₀NO₃.

Synthesis of Compound 259

Using the procedures described for the synthesis of compound 253, withthe exception of substitution by 3-fluoroaniline and no salt formationstep, compound 259 (86 mg) was prepared in 57% yield starting fromcompound 193: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 416.08; C₂₆H₃₉FNO₂.

Synthesis of Compound 260

Using the procedures described for the synthesis of compound 259, withthe exception of substitution by 3-aminopyridine, compound 260 (42 mg)was prepared in 28% yield starting from compound 193: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 399.20;C₂₅H₃₉N₂O₂.

Synthesis of Compound 261

Using the procedures described for the synthesis of compound 259, withthe exception of substitution by m-toluidine, compound 261 (91 mg) wasprepared in 60% yield starting from compound 193: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 412.20;C₂₇H₄₂NO₂.

Example 33

Compound 270, a representative compound of the invention, may beprepared according to the following Reaction Scheme 33. Any number ofcompounds related to compound 270 could be produced using similarmethodology. Starting compound 262 may be prepared according toprocedures described in U.S. Pat. No. 6,046,185.

In general, treatment with TBSCl and imidazole in DMF selectivelyprotects one hydroxyl to give compound 263. NaIO₄ oxidation gives thedialdehyde compound 264. Sodium borohydride reduction gives compound265. Reaction with acetic anhydride and DMAP in pyridine selectivelyprotects one hydroxyl to give compound 266. The free hydroxyl is reactedto give the mesylate compound 267 using MsCl and pyridine. Displacementof the mesylate by the anion of imidazole in DMF gives compound 268.Lithium aluminum hydride removes the acyl group to give compound 269.Treatment with 80% acetic acid removes the TBS group to give compound270.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 263

To a solution of crude compound 262 (86.3 mmol) in DMF (90 mL) and THF(150 mL) that was cooled in a cold water bath were added DMAP (0.50 g,4.1 mmol), imidazole (11.8 g, 173 mmol) and TBSCl (15.6 g, 104 mmol).The mixture was stirred at ambient temperature for 2.5 hours, thencooled in a cold water bath. Water (100 mL) and EtOAc (100 mL) wereadded. The layers were separated and the aqueous portion wasback-extracted with EtOAc (50 mL). The combined organics were washedwith brine (2×250 mL), dried over anhydrous MgSO₄ and concentrated todryness to give compound 263 (38.0 g, quantitative) as a white foam.

Synthesis of Compound 264

To a solution of compound 263 (38.0 g, 86.3 mmol) in THF (250 mL) thatwas cooled in a cold water bath was added a slurry of NaIO₄ (36.9 g, 173mmol) in water (120 mL). The reaction mixture was stirred at ambienttemperature for 1.5 hours, then water (150 mL) and EtOAc (150 mL) wereadded. The layers were separated and the aqueous portion wasback-extracted with EtOAc (100 mL). The combined organics were washedwith brine (200 mL), dried over anhydrous MgSO₄ and concentrated todryness to give crude compound 264 that was used in the next stepwithout further purification.

Synthesis of Compound 265

To a solution of crude compound 264 (86.3 mmol) in THF (125 mL) and MeOH(125 mL) at 0° C. was added NaBH₄ (6.53 g, 173 mmol) in portions. Themixture was stirred at 0° C. for 15 minutes, then at ambient temperaturefor 1 hour. The mixture was cooled in a cold water bath and quenchedwith 80% acetic acid until pH=7.0. Water (100 mL) and EtOAc (150 mL)were added. The layers were separated and the aqueous portion wasback-extracted with EtOAc (100 mL). The combined organics were washedwith brine (200 mL), dried over anhydrous MgSO₄ and concentrated todryness. The residue was stirred with hexanes (150 mL) for 2 hours, thenthe precipitate was filtered out, rinsing with hexanes (2×25 mL). Thesolid was dried to afford compound 265 (19.8 g, 52% from compound 263)as a white solid.

Synthesis of Compound 266

To a solution of compound 265 (17.0 g, 38.9 mmol) in CH₂Cl₂ (25 mL) andpyridine (50 mL) that was cooled in a cold water bath were added DMAP(0.50 g, 4.1 mmol), then acetic anhydride (4.0 mL, 43 mmol) dropwise.The mixture was stirred at ambient temperature for 1.5 hours. Brine (120mL) and EtOAc (250 mL) were added. The layers were separated and theaqueous portion was back-extracted with EtOAc (100 mL). The combinedorganics were washed with brine (2×150 mL), dried over anhydrous MgSO₄and concentrated. The residue was purified by chromatography on silicagel (hexanes/EtOAc, 49:1, 19:1, 9:1, 4:1) to give compound 266 (11.0 g,59%) as a white solid.

Synthesis of Compound 267

To a stirred solution of compound 266 (2.4 g, 5.0 mmol) in pyridine (20mL) was added MsCl (0.39 mL, 5.0 mmol) dropwise. The resulting mixturewas stirred at ambient temperature for 5 hours. The mixture was dilutedwith EtOAc (300 mL), washed with brine, and the aqueous washings werecombined and extracted with EtOAc. The organic extracts were combinedand washed with brine, dried and concentrated to yield compound 267 (2.8g, 100%) as a pale solid.

Synthesis of Compound 268

To a stirred solution of imidazole (66 mg, 0.97 mmol) in DMF (6 mL) atambient temperature was added NaH (39 mg, 60% in mineral oil, 0.97mmol). After stirring for 1 hour at ambient temperature, the mixturebecame clear and compound 267 (200 mg, 0.36 mmol) was added as solid.The mixture was stirred at 60° C. for 3 hours 45 min and then left atambient temperature overnight. The mixture was diluted with toluene (200mL), washed with brine, dried and concentrated. The crude compound 268was used in next step without purification.

Synthesis of Compound 269

To a stirred solution of compound 268 (0.36 mmol) in THF (15 mL) at 0°C. was added 1M LAH in THF (0.57 mL, 0.57 mmol) dropwise. After 5minutes at 0° C., the mixture was stirred at ambient temperature for 5hours. The reaction was cooled to 0° C. again and solid Na₂SO₄.10H₂O(184 mg, 0.57 mmol) was added portionwise. After 5 min at 0° C., themixture was stirred at ambient temperature for 1 hour and then filteredthrough Celite and washed with EtOAc. The filtrate and washings werecombined and concentrated. The crude compound 269 was used in next stepwithout purification

Synthesis of Compound 270

A solution of crude compound 269 (0.36 mmol) in 80% HOAc (4 mL) wasstirred at 40° C. for 6.5 hours. The solvents were removed and theresidue was purified with column chromatography (EtOAc/MeOH/Et₃N,8:1.5:0.5) to afford compound 270 (110 mg, 82% from compound 267). LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)372.87; C₂₃H₃₇N₂O₂.

Example 34

Compounds 276-277, representative compounds of the invention, may beprepared according to the following Reaction Scheme 34. Any number ofcompounds related to compounds 276-277 could be produced using similarmethodology. Starting compound 267 may be prepared according toprocedures described above in Example 33.

In general, azide displacement of the mesylate by NaN₃ in DMF givescompound 271. Base hydrolysis of the acetate gives compound 272. TPAPcatalyzed oxidation of the hydroxyl group gives compound 273. Reductiveamination with cyclopentylamine gives compound 274. Lithium aluminumhydride reduces the azide to give compound 275. Treatment with 80%acetic acid removes the TBS group to give compound 276. After columnpurification, further treatment with 80% acetic acid gives the saltcompound 277.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 271

A mixture of compound 267 (1.8 g, 3.2 mmol) and NaN₃ (420 mg, 6.5 mmol)in DMF (26 ml) was stirred at 60° C. overnight. The mixture was cooledto ambient temperature and diluted with toluene (300 mL), washed withbrine, dried and concentrated to give compound 271 (1.56 g, 95%).

Synthesis of Compound 272

A mixture of compound 271 (1.35 g, 2.68 mmol), K₂CO₃ (2.9 g, 21 mmol) inMeOH/THF/water (50 mL/50 mL/39 mL) was stirred at ambient temperatureovernight. Most of the solvents were removed by rotary evaporation andthe residue was diluted with water (250 mL) and extracted with EtOAc.The EtOAc extracts were combined and washed with brine, dried andconcentrated. The crude product was purified by column chromatography(hexanes/EtOAc, 85:15) to give compound 272 (856 mg) in 69% yield.

Synthesis of Compound 273

To a stirred solution of compound 272 (892 mg, 1.93 mmol) in CH₂Cl₂ (35mL) was added NMO (333 mg, 2.84 mmol) and TPAP (57 mg, 0.16 mmol). Themixture was stirred at ambient temperature for 2 hours 15 min and thenthe solvent was removed by rotary evaporation. The residue was purifiedby column chromatography (hexanes/EtOAc, 9:1) to give compound 273 (769mg) in 87% yield.

Synthesis of Compound 274

To a stirred solution of compound 273 (170 mg, 0.37 mmol) in1,2-dichloroethane (8 mL) were added cyclopentylamine (0.18 mL, 1.8mmol), 4 Å molecular sieves (170 mg), and NaB(OAc)₃H (331 mg, 1.56mmol). The mixture was stirred at ambient temperature for 28 hours andthen filtered through Celite and washed with EtOAc. The filtrate andwashings were combined and concentrated. The residue was filteredthrough silica column with EtOAc/MeOH (9:1), and the crude compound 274was used in next step without further purification.

Synthesis of Compound 275

To a stirred solution of compound 274 (0.37 mmol) in THF (15 mL) at 0°C. was added 1M LAH in THF (1.9 mL, 1.9 mmol) dropwise. After 5 min at0° C., the mixture was stirred at ambient temperature for 5.5 hours. Thereaction was cooled to 0° C. again and solid Na₂SO₄.10H₂O (596 mg, 1.9mmol) was added portionwise. After 5 min at 0° C., the mixture wasstirred at ambient temperature for 1 hour and then filtered throughCelite and washed with EtOAc. The filtrate and washings were combinedand concentrated. The crude compound 275 was used in next step withoutpurification.

Synthesis of Compound 276

A solution of crude compound 275 (0.37 mmol) in 80% HOAc (5 mL) wasstirred at 40° C. for 7.5 hours. The solvents were removed and theresidue was purified by column chromatography (EtOAc/MeOH/water/Et₃N,6.5:2.5:0.5:0.5) to afford compound 276 (74 mg, 52% from compound 273).

Synthesis of Compound 277

A solution of compound 276 (74 mg) in 80% HOAc (0.5 mL) was stirred atambient temperature for a few minutes and then the solvents were removedby rotary evaporation. The residue was co-evaporated with MeOH severaltimes and dried under vacuum. The product was dissolved in a smallamount of MeOH and treated with a small amount of acetonitrile. Thesolvents were removed and the product was dried under vacuum to affordcompound 277 (90 mg, 93%) as off-white powder: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 388.98; C₂₅H₄₅N20.

Example 35

Compounds 282-306, representative compounds of the invention, may beprepared according to the following Reaction Scheme 35. Any number ofcompounds related to compounds 282-306 could be produced using similarmethodology. Starting compound 113 may be prepared according toprocedures described above in Example 12.

In general, reductive amination of a ketone or aldehyde compound such ascompound 113 with an amine such as isobutylamine gives an amine such ascompound 278. Lithium aluminum hydride reduction removes the acyl groupto give compound 279. Treatment with 80% acetic acid removes both theTBS group and the cyclic ketal to give compound 280. Olefination usingMePPh₃Br and KO^(t)Bu in THF gives compound 281. Treatment with 80%acetic acid gives the salt compound 282.

Following are specific examples of the compounds prepared above.

Synthesis of Compound 278

A mixture of compound 113 (0.18 g, 0.35 mmol), isobutylamine (0.18 mL,1.8 mmol) and 4 Å molecular sieves (0.15 g) in DCE (5 mL) was stirred atambient temperature for 1 hour. NaB(OAc)₃H (0.395 g, 1.77 mmol) wasadded and the mixture was stirred at ambient temperature for 5 days. Thereaction mixture was diluted with MeOH and filtered through a celitebed, rinsing with EtOAc. The filtrate was washed with saturated NaHCO₃solution then brine twice, dried over anhydrous MgSO₄ and concentrated.The residue was purified by chromatography on silica gel to give amixture of compound 278 and the imine of compound 278 (0.240 g) as alight yellow oil that was used in the next reaction without furtherpurification.

Synthesis of Compound 279

To a solution of the mixture of compound 278 and its imine (0.33 mmol)in THF (10 mL) was added LiAlH₄ (0.99 mL of a 1 M solution in THF, 0.99mmol). The mixture was stirred at ambient temperature overnight thenquenched with Na₂SO₄.10H₂O and stirred for 30 minutes. The mixture wasfiltered, rinsing with EtOAc, and concentrated to dryness to give crudecompound 279 (0.137 g) as a colourless glass that was used in the nextreaction without further purification.

Synthesis of Compound 280

Crude compound 279 (0.33 mmol) was dissolved in 80% acetic acid (7 mL)and stirred at 40° C. overnight then concentrated. The residue waspartially purified by chromatography on silica gel to give compound 280(0.083 g) as a colourless glass.

Synthesis of Compound 281

A mixture of KO^(t)Bu (0.184 g, 1.56 mmol) and MePPh₃Br (0.557 g, 1.56mmol) in THF (6 mL) was stirred at ambient temperature for 1.5 hours,then a solution of compound 281 (0.083 g, 0.20 mmol) in THF (4 mL) wasadded. The reaction mixture was stirred at ambient temperature overnightthen quenched with saturated NH₄Cl solution and concentrated. Theresidue was partially purified by chromatography on silica gel to affordcompound 281 that was used for the next reaction.

Synthesis of Compound 282

A mixture of compound 281 (0.2 mmol), 80% AcOH and MeOH was concentratedby rotary evaporation. The residue was dissolved in water and washedwith CH₂Cl₂ (5×5 mL) then concentrated. Precipitation from hexanesafforded compound 282 (0.042 g, 28% from compound 113) as a white solid:LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 364.22; C₂₃H₄₂NO₂.

Synthesis of Compound 283

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.329 g (1.47 mmol) NaB(OAc)₃H were used and thereaction time was 4 days, compound 113 (0.25 g, 0.49 mmol) was reactedwith (aminomethyl)pyridine (0.25 mL, 2.5 mmol) to give imineintermediate (0.225 g, 77%, white foam). Using the procedure describedfor the synthesis of compound 279, with the exception that reaction timewas 5 hours, the imine intermediate (0.376 mmol) was reacted with LiAlH₄(1.50 mL of a 1 M solution in Et₂O, 1.50 mmol) to give crude alcoholintermediate with TBS cleaved (0.162 g, yellow foam). Using theprocedure described for the synthesis of compound 280, with theexceptions that 20 mL 80% AcOH were used and the reaction was performedat ambient temperature, the crude alcohol intermediate mixture (0.376mmol) was converted to ketone intermediate (0.095 g, colourless glass).Using the procedure described for the synthesis of compound 281, withthe exceptions that 0.163 g (1.38 mmol) KO^(t)Bu and 0.492 g (1.38 mmol)MePPh₃Br were used and after quenching the reaction mixture was filteredthrough celite, the ketone intermediate (0.23 mmol) was converted to thealkene. Precipitation from Et₂O afforded compound 283 (0.014 g, 7% fromcompound 113) as a white solid. LC/MS (direct infusion, electrospray+ve, 10 mM NH₄OAc in 3:7 water and MeCN) 397.75; C₂₅H₃₈N₂O₂.

Synthesis of Compound 284

Using the procedure described for the synthesis of compound 278,compound 113 (0.18 g, 0.35 mmol) was reacted with ethanolamine (0.11 mL,1.8 mmol) to give amine intermediate (0.053 g, 27%, yellow oil). Usingthe procedure described for the synthesis of compound 279, the amineintermediate (0.096 mmol) was reacted with LiAlH₄ (0.19 mL of a 1 Msolution in THF, 0.19 mmol) to give the alcohol intermediate with someTBS cleavage (0.040 g, colourless glass). Using the procedure describedfor the synthesis of compound 280, with the exceptions that 6 mL 80%acetic acid were used and the residue was not purified, the crudealcohol intermediate mixture was converted to ketone intermediate as theacetic acid salt (0.041 g, colourless glass).

Using the procedure described for the synthesis of compound 281, theketone intermediate (0.096 mmol) was converted to the crude alkene.Using the procedure described for the synthesis of compound 282, withthe exception that the residue was not washed with CH₂Cl₂, the crudealkene was converted to the acetic acid salt. Precipitation fromhexanes/CH₂Cl₂ afforded compound 284 (0.015 g, 10% from compound 113) asa yellow solid. LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAcin 3:7 water and MeCN) 352.12; C₂₁H₃₈NO₃.

Synthesis of Compound 285

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.20 g 4 Å molecular sieves were used, the reactionbegan with 0.395 g (1.77 mmol) NaB(OAc)₃H, then 0.263 g (1.18 mmol) moreNaB(OAc)₃H was added after 2 days and the total reaction time was 6days, compound 113 (0.30 g, 0.59 mmol) was reacted with furfurylamine(0.27 mL, 3.0 mmol) to give a mixture of amine and imine intermediates(0.283 g, white foam). Using the procedure described for the synthesisof compound 279, with the exception that reaction time was 5 hours, theamine/imine intermediate mixture (0.48 mmol) was reacted with LiAlH₄(1.44 mL of a 1 M solution in Et₂O, 1.44 mmol) to give crude alcoholintermediate with most TBS cleaved (0.248 g, yellow oil). Using theprocedure described for the synthesis of compound 280, with theexceptions that 20 mL 80% AcOH were used, the reaction was performed atambient temperature and the residue after purification was dissolved inTHF (6 mL) and treated with 2 N HCl (2 mL) at ambient temperatureovernight then concentrated, the crude alcohol intermediate mixture(0.481 mmol) was converted to ketone intermediate as the HCl salt (0.146g, yellow oil). Using the procedure described for the synthesis ofcompound 281, with the exceptions that 0.236 g (2.00 mmol) KO^(t)Bu and0.715 g (2.00 mmol) MePPh₃Br were used, DMF (0.5 mL) was added and afterquenching the reaction mixture was filtered through celite, the ketoneintermediate (0.33 mmol) was converted to the crude alkene. Using theprocedure described for the synthesis of compound 282, the crude alkenewas converted to the acetic acid salt.

Precipitation from Et₂O afforded compound 285 (0.013 g, 14% fromcompound 113) as a light brown solid. LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 388.16; C₂₄H₃₈NO₃.

Synthesis of Compound 286

Using the procedure described for the synthesis of compound 278, withthe exception that the residue was not purified, compound 113 (0.18 g,0.35 mmol) was reacted with N,N-dimethylethylenediamine (0.20 mL, 1.8mmol) to give a mixture of amine and imine intermediates (0.192 g,colourless oil). Using the procedure described for the synthesis ofcompound 279, the amine/imine intermediate mixture (0.33 mmol) wasreacted with LiAlH₄ (0.99 mL of a 1 M solution in THF, 0.99 mmol) togive crude alcohol intermediate (0.137 g, colourless glass). Using theprocedure described for the synthesis of compound 280, with theexception that the residue was not purified, the crude alcoholintermediate was converted to ketone intermediate as the acetic acidsalt (0.147 g, colourless glass). Using the procedure described for thesynthesis of compound 281, the ketone intermediate (0.33 mmol) wasconverted to the crude alkene. Using the procedure described for thesynthesis of compound 282, with the exception that the residue was notwashed with CH₂Cl₂, the crude alkene was converted to the acetic acidsalt. Concentration from CH₂Cl₂ afforded compound 286 (0.072 g, 47% fromcompound 113) as a light yellow solid: LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 379.03;C₂₃H₄₃N₂O₂.

Synthesis of Compound 287

Using the procedure described for the synthesis of compound 278,compound 113 (0.18 g, 0.35 mmol) was reacted with2-(1-cyclohexenyl)ethylamine (0.25 mL, 1.8 mmol) to give amineintermediate (0.165 g, 77%, yellow oil). Using the procedure describedfor the synthesis of compound 279, the amine intermediate (0.27 mmol)was reacted with LiAlH₄ (0.53 mL of a 1 M solution in THF, 0.53 mmol) togive crude alcohol intermediate (0.132 g, colourless glass). Using theprocedure described for the synthesis of compound 280, with theexception that 8 mL 80% acetic acid were used, the crude alcoholintermediate was converted to ketone intermediate as the acetic acidsalt (0.108 g, colourless glass). Using the procedure described for thesynthesis of compound 281, the ketone intermediate (0.23 mmol) wasconverted to the crude alkene. Using the procedure described for thesynthesis of compound 282, with the exception that the residue waswashed with Et₂O (4×5 mL) instead of CH₂Cl₂, the crude alkene wasconverted to the acetic acid salt. Precipitation from hexanes/CH₂Cl₂afforded compound 287 (0.051 g, 31% from compound 113) as a white solid:LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 416.26; C₂₇H₄₆NO₂.

Synthesis of Compound 288

Using the procedure described for the synthesis of compound 278, withthe exception that the residue was not purified, compound 113 (0.18 g,0.35 mmol) was reacted with 4-(2-aminoethyl)morpholine (0.23 mL, 1.8mmol) to give the amine intermediate (0.205 g, 94%, colourless oil).Using the procedure described for the synthesis of compound 279, theamine intermediate (0.33 mmol) was reacted with LiAlH₄ (0.66 mL of a 1 Msolution in THF, 0.66 mmol) to give crude alcohol intermediate (0.150 g,colourless glass). Using the procedure described for the synthesis ofcompound 280, with the exceptions that 8 mL 80% acetic acid were usedand the residue was not purified, the crude alcohol intermediate wasconverted to ketone intermediate as the acetic acid salt (0.203 g, brownoil). Using the procedure described for the synthesis of compound 281,the ketone intermediate (0.33 mmol) was converted to the crude alkene.Using the procedure described for the synthesis of compound 282, withthe exception that the residue was purified by chromatography on silicagel after washing, the crude alkene was converted to the acetic acidsalt. Precipitation from Et₂O afforded compound 288 (0.108 g, 64% fromcompound 113) as an off-white solid. LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 421.16;C₂₅H₄₅N₂O₃.

Synthesis of Compound 289

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.125 g 4 Å molecular sieves were used, the reactionbegan with 0.329 g (1.47 mmol) NaB(OAc)₃H, then 0.219 g (0.982 mmol)more NaB(OAc)₃H was added after 2 days and the total reaction time was 6days, compound 113 (0.25 g, 0.49 mmol) was reacted with m-toluidine(0.27 mL, 2.5 mmol) to give amine intermediate (0.240 g, yellow oil).Using the procedure described for the synthesis of compound 279, withthe exception that reaction time was 5 hours, the amine intermediate(0.400 mmol) was reacted with LiAlH₄ (0.80 mL of a 1 M solution in Et₂O,0.80 mmol) to give crude alcohol intermediate with most TBS cleaved(0.224 g, yellow oil). Using the procedure described for the synthesisof compound 280, with the exceptions that 20 mL 80% AcOH were used andthe reaction was performed at ambient temperature, the crude alcoholintermediate mixture (0.400 mmol) was converted to ketone intermediate(0.135 g, light brown solid). Using the procedure described for thesynthesis of compound 281, with the exceptions that 0.238 g (2.01 mmol)KO^(t)Bu and 0.719 g (2.01 mmol) MePPh₃Br were used and after quenchingthe reaction mixture was filtered through celite, the ketoneintermediate (0.34 mmol) was converted to the alkene. Concentration fromCH₂Cl₂ gave compound 289 (0.095 g, 49% from compound 113) as a yellowfoam.

Synthesis of Compound 290

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.10 g 4 Å molecular sieves and 6 mL DCE were used,the reaction began with 0.165 g (0.740 mmol) NaB(OAc)₃H, then 0.083 g(0.37 mmol) more NaB(OAc)₃H was added after 8 hours and the totalreaction time was 2 days, compound 113 (0.197 g, 0.387 mmol) was reactedwith benzylamine (0.21 mL, 1.9 mmol) to give amine intermediate (0.171g, 73%, colourless gum). Using the procedure described for the synthesisof compound 279, with the exceptions that 6 mL THF were used andreaction time was 5 hours, the amine intermediate (0.28 mmol) wasreacted with LiAlH₄ (0.56 mL of a 1 M solution in THF, 0.56 mmol) togive crude alcohol intermediate with TBS cleaved (0.132 g, colourlessgum). Using the procedure described for the synthesis of compound 280,with the exceptions that the alcohol was treated with 2 N HCl (2 mL) inTHF (6 mL) instead of 80% acetic acid and the reaction was performed atambient temperature, the crude alcohol intermediate mixture (0.28 mmol)was converted to ketone intermediate (0.095 g, colourless glass). Usingthe procedure described for the synthesis of compound 281, with theexceptions that 0.162 g (1.44 mmol) KO^(t)Bu, 0.514 g (1.44 mmol)MePPh₃Br and 13 mL THF were used and after quenching the reactionmixture was diluted with EtOAc (20 mL) and MeOH (10 mL) then filteredthrough celite, the ketone intermediate (0.24 mmol) was converted to thealkene.

Precipitation from ACN gave compound 290 (0.063 g, 41% from compound113) as a white solid. LC/MS (direct infusion, electrospray +ve, 10 mMNH₄OAc in 3:7 water and MeCN) 382.06; C₂₅H₃₆NO₂.

Synthesis of Compound 291

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by 3-fluorobenzylamine, compound 291(0.039 g) was prepared as a yellow solid in 23% yield starting fromcompound 95: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 416.21; C₂₆H₃₉FNO₂.

Synthesis of Compound 292

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by morpholine, compound 292 (0.089 g) wasprepared as a light pink solid in 58% yield starting from compound 95.LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 378.12; C₂₃H₄₀NO₃.

Synthesis of Compound 293

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by 3,4-(methylenedioxy)aniline, compound293 (0.068 g) was prepared as a white solid in 45% yield starting fromcompound 95. LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 428.37; C₂₆H₃₈NO₄.

Synthesis of Compound 294

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by isobutylamine, compound 294 (0.111 g)was prepared as a orange solid in 75% yield starting from compound 95.LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 364.12; C₂₃H₄₂NO₂.

Synthesis of Compound 295

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by cyclohexylamine, compound 295 (0.029 g)was prepared as a orange solid in 18% yield starting from compound 95.LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 390.12; C₂₅H₄₂NO₂.

Synthesis of Compound 296

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by N-methylaniline, compound 296 (0.040 g)was prepared as a orange solid in 28% yield starting from compound 95.LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 397.86; C₂₆H₄₀NO₂.

Synthesis of Compound 297

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.20 g of 4 Å molecular sieves and 7 mL DCE wereused, the mixture was stirred for 1 hour before NaB(OAc)₃H was added,reaction time was 3 days and the residue was purified by chromatographyon silica gel (hexanes/EtOAc, 1:1; EtOAc/MeOH, 9:1), compound 95 (0.25g, 0.49 mmol) was reacted with 3-(aminomethyl)pyridine (0.25 mL, 2.5mmol) to give amine intermediate (0.266 g, 90%, colourless glass). Usingthe procedure described for the synthesis of compound 279, with theexception that reaction time was overnight, the amine intermediate (0.44mmol) was reacted with LiAlH₄ (0.98 mL of a 1 M solution in Et₂O, 0.98mmol) to give alcohol intermediate (0.255 g, yellow foam). Using theprocedure described for the synthesis of compound 280, with theexceptions that 20 mL 80% AcOH were used, the reaction was run atambient temperature for 4 days and the product was residue was purifiedby chromatography on silica gel (EtOAc/MeOH/H₂O/Et₃N, 9:1:0.25:0.25),the alcohol intermediate (0.46 mmol) was converted to ketoneintermediate as the free amine (0.039 g, light brown solid). Using theprocedure described for the synthesis of compound 281, with theexceptions that 0.069 g (0.58 mmol) KO^(t)Bu, 0.209 g, (0.585 mmol)MePPH₃Br and 7 mL THF were used, the reaction was stirred for 1 hourbefore the ketone intermediate solution was added and reaction time was2 days, the ketone intermediate (0.097 mmol) was converted to the crudealkene. Using the procedure described for the synthesis of compound 282,with the exception that the residue was not purified by chromatography,the crude alkene was converted to compound 297 (0.011 g, 5% fromINT1703) as a yellow glass. LC/MS (direct infusion, electrospray +ve, 10mM NH₄OAc in 3:7 water and MeCN) 399.16; C₂₅H₃₉N₂O₂.

Synthesis of Compound 298

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.20 g of 4 Å molecular sieves and 7 mL DCE wereused, the mixture was stirred for 1 hour before NaB(OAc)₃H was added,reaction time was 3 days and the residue was purified by chromatographyon silica gel (hexanes/EtOAc, 3:2, 1:1), compound 95 (0.25 g, 0.49 mmol)was reacted with furfurylamine (0.23 mL, 2.5 mmol) to give amineintermediate (0.269 g, 93%, yellow foam). Using the procedure describedfor the synthesis of compound 279, the amine intermediate (0.46 mmol)was reacted with LiAlH₄ (0.98 mL of a 1 M solution in Et₂O, 0.98 mmol)overnight then 1.96 mL more LiAlH₄ solution (1 M in Et₂O, 1.96 mmol)were added before further reaction overnight to give alcoholintermediate (0.228 g, white foam). Using the procedure described forthe synthesis of compound 280, with the exceptions that 20 mL 80% AcOHwere used and the reaction was run at ambient temperature for 3 days,the alcohol intermediate (0.42 mmol) was converted to ketoneintermediate as the acetic acid salt (0.229 g, yellow glass). Using theprocedure described for the synthesis of compound 281, with theexception that 0.2 mL DMF were added, the ketone intermediate (0.42mmol) was converted to the crude alkene. Using the procedure describedfor the synthesis of compound 282, the crude alkene was converted to theacetic acid salt. Precipitation from Et₂O afforded compound 298 (0.088g, 40% from compound 95) as an orange solid. LC/MS (direct infusion,electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 388.05; C₂₄H₃₈NO₃.

Synthesis of Compound 299

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.20 g of 4 Å molecular sieves and 7 mL DCE wereused, the mixture was stirred for 1 hour before NaB(OAc)₃H was added,reaction time was 3 days and the residue was purified by chromatographyon silica gel (EtOAc; EtOAc/MeOH/Et₃N, 9:1:0.3), compound 95 (0.25 g,0.49 mmol) was reacted with ethanolamine (0.15 mL, 2.5 mmol) to giveamine intermediate (0.274 g, quantitative, yellow foam). Using theprocedure described for the synthesis of compound 279, the amineintermediate (0.49 mmol) was reacted with LiAlH₄ (0.98 mL of a 1 Msolution in Et₂O, 0.98 mmol) overnight then 0.98 mL more LiAlH₄ solution(1 M in Et₂O, 0.98 mmol) were added before further reaction overnight togive alcohol intermediate (0.224 g, colourless glass). Using theprocedure described for the synthesis of compound 280, with theexceptions that 20 mL 80% AcOH were used and the reaction was run atambient temperature for 3 days, the alcohol intermediate (0.44 mmol) wasconverted to ketone intermediate as the acetic acid salt (0.216 g,colourless glass). Using the procedure described for the synthesis ofcompound 281, with the exception that 0.5 mL DMF were added, the ketoneintermediate (0.44 mmol) was converted to the crude alkene. Using theprocedure described for the synthesis of compound 282, with theexception that the residue was not purified by chromatography, the crudealkene was converted to the acetic acid salt. Concentration from CH₂Cl₂afforded compound 299 (0.041 g, 20% from compound 95) as a yellow solid.LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 352.06; C₂₁H₃₈NO₃.

Synthesis of Compound 300

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.10 g of 4 Å molecular sieves were used, reactiontime was 2.5 days and the residue was purified by chromatography onsilica gel (hexanes/EtOAc, 8:2), compound 95 (0.10 g, 0.20 mmol) wasreacted with m-toluidine (0.10 mL, 0.93 mmol) to give amine intermediate(0.091 g, 77%, yellowish gum). Using the procedure described for thesynthesis of compound 279, with the exceptions that 8 mL THF were used,LiAlH₄ solution was added at 0° C. and the mixture was stirred at 0° C.for 20 minutes before stirring at ambient temperature, and reaction timewas 3.5 hours, the amine intermediate (0.15 mmol) was reacted withLiAlH₄ (0.45 mL of a 1 M solution in THF, 0.45 mmol) to give crudealcohol intermediate. Using the procedure described for the synthesis ofcompound 280, with the exceptions that 4 mL 80% AcOH were used andreaction time was 5 hours, the crude alcohol intermediate (0.15 mmol)was converted to crude ketone intermediate. Using the proceduredescribed for the synthesis of compound 281, with the exceptions that 7mL THF and 0.5 mL DMF were used and after quenching the mixture wasdiluted with EtOAc (20 mL) and MeOH (5 mL) then filtered through celite,the ketone intermediate (0.15 mmol) was converted to alkene (0.021 g,pale gum). Using the procedure described for the synthesis of compound282, with the exception that the residue was not purified bychromatography, the alkene was converted to the acetic acid salt.Precipitation from ACN/MeOH afforded compound 300 (0.020 g, 21% fromcompound 95) as a yellow foam.

Synthesis of Compound 301

Using the procedure described for the synthesis of compound 278, withthe exceptions that 0.10 g of 4 Å molecular sieves were used, reactiontime was 2.5 days and the residue was purified by chromatography onsilica gel (EtOAc/MeOH, 9:1), compound 95 (0.10 g, 0.20 mmol) wasreacted with pyrrolidine (0.10 mL, 1.2 mmol) to give amine intermediate(0.090 g, 82%, clear gum). Using the procedure described for thesynthesis of compound 279, with the exceptions that 8 mL THF were used,LiAlH₄ solution was added at 0° C. and the mixture was stirred at 0° C.for 20 minutes before stirring at ambient temperature, and reaction timewas 3.5 hours, the amine intermediate (0.16 mmol) was reacted withLiAlH₄ (0.45 mL of a 1 M solution in THF, 0.45 mmol) to give crudealcohol intermediate. Using the procedure described for the synthesis ofcompound 280, with the exceptions that 4 mL 80% AcOH were used andreaction time was 5 hours, the crude alcohol intermediate (0.16 mmol)was converted to crude ketone intermediate. Using the proceduredescribed for the synthesis of compound 281, with the exceptions that 7mL THF and 0.5 mL DMF were used and after quenching the mixture wasdiluted with EtOAc (20 mL) and MeOH (5 mL), then filtered throughcelite, the ketone intermediate (0.16 mmol) was converted to alkene(0.029 g, gum). Using the procedure described for the synthesis ofcompound 282, with the exception that the residue was not purified bychromatography, the alkene was converted to the acetic acid salt.Precipitation from ACN/MeOH afforded compound 301 (0.038 g, 42% fromINT1703) as an off-white foam. LC/MS (direct infusion, electrospray +ve,10 mM NH₄OAc in 3:7 water and MeCN) 362.18; C₂₃H₄₀NO₂.

Synthesis of Compound 302

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by N,N-dimethylethylenediamine, compound302 (0.067 g) was prepared as a orange solid in 39% yield starting fromcompound 205: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 393.03; C₂₄H₄₅N₂O₂.

Synthesis of Compound 303

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by 3,4-(methylenedioxy)aniline, compound303 (0.055 g) was prepared as a orange solid in 33% yield starting fromcompound 205: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 441.95; C₂₇H₄₀NO₄.

Synthesis of Compound 304

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by cyclohexylamine, compound 304 (0.022 g)was prepared as a light yellow solid in 12% yield starting from compound205: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 waterand MeCN) 404.05; C₂₆H₄₆NO₂.

Synthesis of Compound 305

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by 3-trifluoromethylaniline, compound 305(0.096 g) was prepared as a white solid in 54% yield starting fromcompound 205: LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in3:7 water and MeCN) 465.45; C₂₇H₃₈F₃NO₂.

Synthesis of Compound 306

Using the procedures described for the synthesis of compound 282, withthe exception of substitution by isobutylamine, compound 306 (0.035 g)was prepared as a white solid in 21% yield starting from compound 205:LC/MS (direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water andMeCN) 378.08; C₂₄H₄₄NO₂.

Example 36

Compounds 308-310, representative compounds of the invention, may beprepared according to the following Reaction Scheme 36. Any number ofcompounds related to compounds 308-310 could be produced using similarmethodology. Starting compound 217 may be prepared according to theprocedure described above in Example 24.

In general, reductive amination of compound 217 gives compound 307. Areducing agent, such as lithium aluminum hydride, is used to reduce theester-protected hydroxyls to give compound 305. Treatment with 80%acetic acid form the ammonium acetate salt of compound 309.

Synthesis of Compound 307

A mixture of compound 217 (0.20 g, 0.49 mmol), pyrrolidine (0.18 mL, 2.2mmol) and 4 Å molecular sieves (0.20 g) in DCE (5 mL) was stirred atambient temperature for 30 minutes. NaB(OAc)₃H (0.297 g, 1.33 mmol) wasadded, rinsing with DCE (2 mL), and the mixture was stirred at ambienttemperature overnight. The reaction mixture was diluted with MeOH (3 mL)and filtered through a celite bed, rinsing with EtOAc (25 mL). Thefiltrate was washed with saturated NaHCO₃ solution (10 mL), then brine(2×5 mL), dried over anhydrous MgSO₄ and concentrated to give compound307 (0.235 g, quantitative) as a colourless glass that was used in thenext reaction without further purification.

Synthesis of Compound 308

To a solution of compound 307 (0.49 mmol) in THF (10 mL) was addedLiAlH₄ (0.88 mL of a 1 M solution in THF, 0.88 mmol). The mixture wasstirred at ambient temperature overnight, then quenched withNa₂SO₄.10H₂O and stirred for 1 hour. The mixture was filtered, rinsingwith EtOAc, and concentrated to dryness. The residue was purified bychromatography on silica gel (EtOAc/MeOH, 9:1; EtOAc/MeOH/Et₃N,9:0.75:0.25) to give compound 308 as a white solid that was used for thenext reaction.

Synthesis of Compound 309

A mixture of compound 308, 80% AcOH (1 mL) and MeOH (5 mL) wasconcentrated by rotary evaporation. Concentration from CH₂Cl₂ affordedcompound 309 (0.168 g, 79% from INT5) as a white foam: LC/MS (directinfusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN) 375.95;C₂₄H₄₂NO₂.

Synthesis of Compound 310

Using the procedures described for the synthesis of compound 309, withthe exception of substitution by m-toluidine, compound 310 (0.20 g) wasprepared as a yellow foam in 69% yield starting from compound 217. LC/MS(direct infusion, electrospray +ve, 10 mM NH₄OAc in 3:7 water and MeCN)412.01; C₂₇H₄₂NO₂.

The following compounds of the invention were prepared according to theforegoing Examples:

-   Compound 25;    5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 29;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 38;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-hydroxyethyl)-7aβmethyl-1-methyleneoctahydroindene;-   Compound 45;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 51;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 59;    5-(1β-methyl-4β-amino-2β-hydroxymethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 67;    5-(1β-methyl-4β-hydroxy-2β-(2-aminoethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 68;    5-(1β-methyl-4β-hydroxy-2β-(2-aminoethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-ethylideneoctahydroindene,    ammonium acetate salt;-   Compound 77;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 78;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 79;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-indene,    ammonium chloride salt;-   Compound 80;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium chloride salt;-   Compound 81;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβmethyl-1-ethylideneoctahydroindene,    ammonium chloride salt;-   Compound 88;    5-(1β-methyl-4β-hydroxy-2β-aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 89;    5-(1β-methyl-4β-hydroxy-2β-aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 100;    5-(1β-methyl-4β-hydroxy-2β-aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 101;    5-(1β-methyl-4β-hydroxy-2β-aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 107;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-aminoethyl)-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 108;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-aminoethyl)-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 119;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 120;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-aminomethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 132;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1-difluoromethyleneoctahydroindene;-   Compound 133;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβmethyl-1-difluoromethyleneoctahydroindene,    ammonium chloride salt;-   Compound 143;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1-dichloromethyleneoctahydroindene,    ammonium chloride salt;-   Compound 157; 5-(1    (3-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1β-(propen-2-yl)octahydroindene;-   Compound 158;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβmethyl-1β-(propen-2-yl)octahydroindene,    ammonium acetate salt;-   Compound 163;    5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-3a,4,5,6,7,7a-hexahydro-3H-indene;-   Compound 178;    5-(1β-methyl-4α,5α-dihydroxy-2β-hydroxymethylcyclohexyl)-4α-aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 182;    5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminoprop-1-enyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 183;    5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminoprop-1-enyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 184;    5-(1β-methyl-4β-hydroxy-2β-(2-(4-chlorophenyl)ethyl)cyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 185;    5-(1β-methyl-4β-hydroxy-2β-(2-pyridin-3-ylethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 189;    5-(1β-methyl-4β-hydroxy-2β-ethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 192;    5-(1β-methyl-4β-hydroxy-2β-(2-(4-ethoxyphenyl)eth-1-en-1-yl)cyclohexyl)-4α-acetoxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 195;    5-(1β-methyl-4β-hydroxy-2β-(2-(pyridin-2-yl)eth-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 196;    5-(1β-methyl-4β-hydroxy-2β-(2-(pyridin-3-yl)eth-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 197;    5-(1β-methyl-4β-hydroxy-2β-(hept-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 198;    5-(1β-methyl-4β-hydroxy-2β-(4-benzyloxybut-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 199;    5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminoprop-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 200;    5-(1β-methyl-4β-hydroxy-2β-(2-(4-chlorophenyl)ethenyl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 201;    5-(1β-methyl-4β-hydroxy-2β-(4-hydroxybut-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβmethyl-1-methyleneoctahydroindene;-   Compound 203;    5-(1β-methyl-4β-hydroxy-2β-(3-hydroxyprop-1-en-1-yl)cyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 210;    5-(1β-methyl-4β-hydroxy-2β-(3-(4-chlorophenyl)prop-2Z-en-1-yl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 211;    5-(1β-methyl-4β-hydroxy-2β-(3-(4-chlorophenyl)prop-2E-en-1-yl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 212;    5-(1β-methyl-4β-hydroxy-2β-(4-dimethylamino/but-1-en-1-yl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 219;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(4-dimethylaminobut-2Z-en-1-yl)-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 220;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(4-dimethylaminobut-2Z-en-1-yl)-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 221;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(3-pyridin-3-ylprop-2Z-en-1-yl)-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 222;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(3-pyridin-3-ylprop-2E-en-1-yl)-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 225;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(methylsulfonyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 227;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(acetyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 229;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(ethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 231;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(benzyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 232;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(benzyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 233;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(cyclopropylmethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 235;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(dimethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 236;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(dimethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 240;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(methyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 241;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(methyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 242;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(guanidino)methyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium chloride salt;-   Compound 243;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(2-methylpropyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 244;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(2-methylpropyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 245;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(1β-methylpiperidin-4-yl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium diacetate salt;-   Compound 246;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(3-nitrobenzyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 247;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(piperonyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 248;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(pyrrol-2-ylmethyl)aminomethyl-7αβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 249;    5-(1βmethyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(furfuryl)aminomethyl-7a3β-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 250;    5-(1β-methyl-4-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(pyridin-3-ylmethyl)aminomethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 252;    5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 253;    5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 254;    5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 255;    5-(1β-methyl-4β-hydroxy-2β-(2-dimethylaminoethyl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 256;    5-(1β-methyl-4β-hydroxy-2β-(cyclohexyl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 257;    5-(1β-methyl-4β-hydroxy-2β-(pyridin-3-ylmethyl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 258;    5-(1β-methyl-4β-hydroxy-2β-(furfuryl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 259;    5-(1β-methyl-4β-hydroxy-2β-(3-fluorophenyl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβmethyl-1-methyleneoctahydroindene;-   Compound 260;    5-(1β-methyl-4β-hydroxy-2β-(pyridin-3-yl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 261;    5-(1β-methyl-4β-hydroxy-2β-(3-methylphenyl)aminomethylcyclohexyl)-4α-hydroxymethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 270;    5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcyclohexyl)-4α-(imidazol-1-yl)methyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 276;    5-(1β-methyl-4β-hydroxy-2β-(cyclopentyl)aminomethylcyclohexyl)-4α-aminomethyl-7aβmethyl-1-methyleneoctahydroindene;-   Compound 277;    5-(1β-methyl-4β-hydroxy-2β-(cyclopentyl)aminomethylcyclohexyl)-4α-aminomethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium diacetate salt;-   Compound 282;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-methylpropyl)aminomethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 283;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(pyridin-3-ylmethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 284;    5-(1β-methyl-2,41-dihydroxycyclohexyl)-4α-(2-hydroxyethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 285;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(furfuryl)aminomethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 286;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-dimethylaminoethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 287;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-cyclohex-1-en-1-ylethyl)aminomethyl-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 288;    5-(1β-methyl-23,41-dihydroxycyclohexyl)-4α-(2-morpholin-4-ylethyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 289;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(3-methylphenyl)aminomethyl-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 290;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(benzyl)aminomethyl-7aβmethyl-1-methyleneoctahydroindene;-   Compound 291;    5-(1β-methyl-4β-hydroxy-2β-(3-fluorobenzyl)aminomethylcyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 292;    5-(1β-methyl-4β-hydroxy-2β-(morpholin-4-yl)methylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 293;    5-(1β-methyl-4β-hydroxy-2β-(1,3-benzodioxol-5-yl)aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 294;    5-(1β-methyl-4β-hydroxy-2β-(2-methylpropyl)aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 295;    5-(1β-methyl-4β-hydroxy-2β-(cyclohexyl)aminomethylcyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 296;    5-(1β-methyl-4β-hydroxy-2β-(N-phenyl-N-methylamino)methylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 297;    5-(1β-methyl-4β-hydroxy-2β-(pyridin-3-ylmethyl)aminomethylcyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 298;    5-(1β-methyl-4β-hydroxy-2β-(furfuryl)aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 299;    5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 300;    5-(1β-methyl-4β-hydroxy-2β-(3-methylphenyl)aminomethylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 301;    5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 302;    5-(1β-methyl-4β-hydroxy-2β-(2-(2-dimethylaminoethyl)aminoethyl)cyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 303;    5-(1β-methyl-4β-hydroxy-2β-(2-(1,3-benzodioxol-5-yl)aminoethyl)cyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene;-   Compound 304;    5-(1β-methyl-4β-hydroxy-2β-(2-(cyclohexyl)aminoethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 305;    5-(1β-methyl-4β-hydroxy-2β-(2-(3-trifluoromethylphenyl)aminoethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 306;    5-(1β-methyl-4β-hydroxy-2β-(2-(2-methylpropyl)aminoethyl)cyclohexyl)-4α-hydroxy-7aβmethyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 308;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-pyrrolidin-1-ylethyl)-7aβ-methyl-1-methyleneoctahydroindene;-   Compound 309;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-pyrrolidin-1-ylethyl)-7aβ-methyl-1-methyleneoctahydroindene,    ammonium acetate salt;-   Compound 310;    5-(1β-methyl-2β,4β-dihydroxycyclohexyl)-4α-(2-(3-methylphenyl)aminoethyl)-7aβ-methyl-1-methyleneoctahydroindene.

All compounds of the invention as prepared above which exist in freebase or acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic base oracid. Salts of the compounds prepared above may be converted to theirfree base or acid form by standard techniques.

UTILITY EXAMPLES Example A Effect of Compounds on Ear Edema in a TH1Mouse Model of Chemical Hapten Delayed Type Hypersensitivity

Delayed type hypersensitivity models are T cell dependent responses. Thetype of chemical hapten used can bias the T cell response towards apredominantly TH1 or TH2 polarization. Oxazolone anddi-nitro-chloro-benzene (DNCB) induce a TH1 dominant immune response.

Mice are sensitized on day 0 by epicutaneous application of 100 μL 3%oxazolone solution in 95% ethanol on the shaved abdomen. This procedureis repeated on day 1. Six days after sensitization (i.e., on day 5),mice are challenged by topically painting 25 μL 0.8% oxazolone dissolvedin 95% ethanol on both sides of the right ears and 25 μL of 95% ethanolon the left ears. On day 6 (24 hours after challenge), mice aresacrificed, both ears are removed and a standard disc of tissue isharvested immediately from each ear using a cork borer. Care is taken tosample the tissues from the same ear area. The weight of the ear disctissues is immediately measured. Test compounds are administered orallyat a dose of 5 mg/kg once daily for 7 days (from day 0 to day 6) withthe last dose 2 hours prior to sacrifice.

Alternatively, mice are sensitized on day 0 by epicutaneous applicationof 50 μL 1% di-nitrochlorobenzene (DNCB) solution in 4: ratio ofacetone:olive oil on the shaved abdomen. This procedure is repeated onday 5. Starting eleven days after the initial sensitization, mice arechallenged 3 times (on days 10, 11, and 12) by topically painting 25 μL0.5% DNCB dissolved in a 4:1 ratio of acetone:olive oil on both sides ofthe right ears and 25 μL of vehicle on the left ears. Twenty-four hoursafter challenge, mice are sacrificed as described above. Test compoundsare administered orally at a dose of 10 mg/kg once daily for 5 days(from day 8 to day 12) with the last dose 2 hours prior to challenge.

Ear edema is expressed as increase in ear weight, and calculated bysubtracting the left ear weight (challenged with vehicle) from that ofright ear (challenged with chemical hapten). The percentage inhibitionof the ear edema by drugs is calculated using following equation:100−((drug edema/mean control edema)*100).

Compounds of the invention may be tested in this assay to show theirability to inhibit oxazolone and DNCB induced dermal inflammation.

Example B Effect of Compounds on Ear Edema in a TH2 Mouse Model ofDelayed Type Hypersensitivity to Fluorescein Isothiocyanate

Mice are sensitized on day 0 by epicutaneous application of 50 μL 0.5%fluorescein isothiocyanate (FITC) solution in 1:1 acetone and dibutylphthalate on the shaved abdomen. This procedure is repeated on day 7.Fourteen days after sensitization (i.e., on day 13), mice are challengedby topically painting 25 μL 0.5% FITC dissolved in 1:1 acetone anddibutyl phthalate on both sides of the right ears and 25 μL 1:1 acetoneand dibutyl phthalate solution on the left ears. On day 14 (24 hoursafter challenge), mice are sacrificed, both ears are removed and astandard disc of tissue is harvested immediately from each ear using acork borer. Care is taken to sample the tissues from the same ear area.The weight of the ear disc tissues is immediately measured. Testcompounds (5-10 mg/kg) or vehicle is administered orally once daily for3 days (from day 11 to day 13) 2 hours prior to challenge.

Ear edema is expressed as increase in ear weight, and calculated bysubtracting the left ear weight (challenged with vehicle) from that ofright ear (challenged with FITC). The percentage inhibition of the earedema by drugs is calculated using the following equation: 100-((drugedema/mean control edema)*100).

Compounds of the invention, when tested in this assay, were shown toinhibit FITC induced dermal inflammation at doses of less than 20 mg/kg.

Example C Effect of Compounds on LPS-Induced Peritonitis in Mouse

Mice are administered drug (5 mg/kg) or vehicle orally q.d. for fourdays with the last dose 2 hours prior to challenge. On day 4, mice arechallenged with either saline or lipopolysaccharide (LPS) dissolved insaline (4 mg/kg) via intra-peritoneal injection. At 24 h or 48 h postchallenge, animals are anesthetized, and euthanized by trans-thoraciccardiac exsanguination. The peritoneal cavity is lavaged with ice-coldEDTA containing phosphate buffered saline (PBS). The peritoneal lavagefluid is centrifuged and the supernatant removed. The pellet isresuspended in PBS at 4° C. Cytospins are prepared and stained formanual differentiation and enumeration of cell types. In addition, theresuspended lavage fluid is analyzed for absolute cell numbers and celldifferentials by the CellDyn 3700SC hematology analyzer (AbbottLaboratories Inc.).

Compounds of the invention, when tested in this assay, were shown toinhibit LPS induced peritoneal inflammation at doses of less than 20mg/kg.

Example D

Effect of Compounds on Cartilage Degradation in Mice

This model is used to investigate the effect of novel compounds oncartilage degradation induced by the natural inflammatory responsecreated by implantation of a foreign body. Activity in this model may beindicative of activity in arthritis.

Zyphoid sternum cartilage is excised from CO₂ terminated rats, washed inHibitane, and rinsed in sterile, phosphate buffered saline. A 4 cmdiameter disc is removed from the sternum with a #4 stainless steelleather hole punch, and cut in half.

Each half is weighed and wrapped in pre-weighed, moist, sterile cottonbefore implantation. A piece of cotton wrapped cartilage is implantedsubcutaneously into each dorsolateral surface of anaesthetized femaleCD/1 mice (aged 6-8 weeks) via a 1 cm incision along the dorsal midline(Day 0). Mice are administered test articles by oral administration ondays 3 to 17. On day 18, mice are sacrificed, the cotton and cartilageremoved, and the cartilage separated from the cotton. Both the cartilageand the cotton are weighed, and differences between pre and post implantweights are calculated. The cotton is rinsed in 1 mL of buffer, andcytospins are prepared and stained for differentiation and enumerationof cell types. In addition, the resuspended lavage fluid is analyzed forabsolute cell numbers and cell differentials by the CellDyn 3700SChematology analyzer (Abbott Laboratories Inc.).

The cartilage is digested overnight in a papain and cysteinehydrochloric acid solution at 65° C. and glucosaminoglycan contentremaining in the cartilage is assayed by spectrophotometrically andcalculated as % GAG/mg of cartilage degraded (normalized to pre implantcartilage weight).

Compounds of the invention may be tested in this assay to show theirability to inhibit cartilage degradation.

Example E Effect of Compounds on Irritant-Induced Mouse Ear Edema

A number of mice are uniquely identified by placing a mark with anindelible marker on their tail. Mice are dosed orally with 15 mg/kg testcompound in 100 μL of 45% β-cyclodextrin in saline. Mice are brieflyanaesthesized with 2% halothane, and 2 g of phorbol 12-myristate13-acetate (PMA) in 25 μl of acetone is applied to the inner and outersides of the left ear of the mouse. Acetone is applied to the right earof the mouse in the same manner to serve as a vehicle control. Controlanimals receive the same treatment but without any test compound. After3 hours, mice are sacrificed by cervical dislocation, and a standardsized biopsy is excised from the ears and weighed to the nearest 1/10thof a mg. Data are analyzed by taking the difference of each left earfrom the right ear, and then calculating the % inhibition of edema by(((mean Rx/mean irritant))×100)−100.

Compounds of the invention may be tested in this assay to show theirability to inhibit PMA induced dermal edema.

Example F Effect of Compounds on Cytokine-Induced TransendothelialMigration of Leukocytes

The Flow Chamber assay allows for an in vitro analysis of the effects oftest compounds on leukocyte adhesion to human endothelium. Using aparallel plate flow chamber, human blood is perfused at physiologicalrates across an inflamed HUVEC monolayer.

HUVEC monolayers are prepared at passage 3 in 35 mm tissue culturedishes coated with 2% gelatin and 5 μg/mL fibronectin. Following 3 days,confluent monolayers are treated with 25 μg/mL of TNF-α for 4 hours.Test compound is added as required for appropriate incubation times (10min or 4 hr). Blood is collected from healthy human adults, drawn intoVacutainers with sodium heparin, and maintained at 37° C. Blood istreated with various concentrations of test compound for 10 min at 37°C. The whole blood is then perfused through the flow chamber for 2 minat a shear force of 10 dynes/cm². Monolayers are then washed with HBSSat 37° C. for approximately 6 min at 10 dynes/cm². Monolayers are videotaped at the start of the wash period. During the last 5 min of the washperiod, rolling, adherent, and transmigrated leukocytes are manuallycounted at 20× objective within two fields of view every minute.Adherent leukocytes are defined as being stationary for a minimum of 10seconds. Data from each minute is averaged and defined as a percentinhibition against the vehicle treated, TNF-α stimulated, sample.Efficacy of drug articles is compared to a gold standard control sampleprepared by treating a HUVEC monolayer with an anti-human E-selectinantibody (10 μg/mL) and the blood with a rat anti-human CD18 antibody(20 μg/mL), both for 10 min at 37° C.

Compounds of the invention, when tested in this assay, were shown toinhibit TNF-α induced transendothelial migration at concentrations ofless than 20 μM.

Example G Effect of Compounds on Allergen-Induced Lung Inflammation inthe Rat

The ability of a compound to inhibit the allergen-induced accumulationof inflammatory cells such as eosinophils and neutrophils in the lavagefluid obtained from sensitized animals is indicative of that compound'santi-asthma activity. In particular, this model system is useful in theevaluation of the effects of a test compound in the treatment of thelate phase response of asthma, when lung inflammation and the secondphase of bronchoconstriction is apparent, and in allergy, especiallywhere it affects the respiratory system. The test is conducted asfollows.

Male Brown Norway rats are sensitized to ovalbumin by singleintraperitoneal injection of 1 mg ovalbumin adsorbed to 100 mg Al(OH)₃(alum) in 1 mL sterile saline (saline control rats receive only sterilesaline) on day 1, and allowed to sensitize until day 21. Test compoundsare given orally q.d. for three days prior to challenge (days 19, 20,21), and one day post challenge (day 22), with the third dose given 2hours before challenge, and the fourth day dose given 24 hours afterchallenge (volume=300 μl/dose). Rats are challenged with 5% ovalbumin insaline generated using a Devillbis nebulizer for 5 min on day 21.

Forty-eight hours after challenge, animals are sacrificed with anoverdose of intraperitoneally-delivered sodium pentobarbitol and thelungs are lavaged with cold 2×7 mL phosphate buffered saline. Therecovered lavage fluid is placed on ice. The bronchoalveolar lavagefluid is centrifuged and the supernatant removed. The pellet isresuspended in phosphate buffered saline at 4° C. Cytospins are preparedand stained for differentiation and enumeration of cell types. Compoundsof the invention were shown to inhibit allergen induced lunginflammation at doses of less than 20 mg/kg.

Compounds of the invention, when tested in this assay, were shown toinhibit allergen induced lung inflammation at doses of less than 20mg/kg.

Example H Effect of Compounds on Allergen-Induced Bronchoconstriction inthe Mouse

The Buxco murine airway hyper-responsiveness (AHR) model has been wellcharacterized by numerous investigators, and mimics the severe airwayconstriction in response to aerosol challenges that sensitized animalsexhibit compared to unsensitized animals. The Buxco system uses atechnique called whole body plethysmography, in which breathing-inducedchanges in chamber pressure are quantified using the correlation betweenincreased airway resistance and increased expiratory time/breathingpause to calculate the degree of airway constriction (Penh).

Following allergen sensitization and inhalation challenge of the airway,the Penh will increase compared to sham sensitized, sham challengedanimals. Thus the effectiveness of a potential anti-inflammatory agentcan be determined by examining its impact on ovalbumin induced AHR.

Female Balb/c mice are sensitized on day 1 and 14 by i.p. injection of100 μL sterile saline containing 20 μg ovalbumin and 2.25 mg Al(OH)₃.Sham sensitized mice receive 100 μL sterile saline alone. Test compounds(5 mg/kg) are administered by oral gavage on five consecutive days, twodays before challenge (days 26 and 27) and on the three days ofovalbumin challenge (days 28, 29 and 30, 2 hours before challenge). Miceare challenged with aerosolized ovalbumin (5% in saline) for 20 min ondays 28, 29 and 30. On day 31, mice are placed in the whole bodyplethysmography chambers of the Buxco system and airway reactivity toaerosolized PBS and methacholine (MCh; 0.78, 1.56, 3.125, 6.25, 12.5,25, 50 mg/mL) challenge is measured as Penh.

Compounds of the invention, when tested in this assay, were shown toinhibit allergen induced airway hyper-reactivity at doses of less than20 mg/kg.

Example I Effect of Compounds on LPS-Induced Acute Lung Inflammation inRat

Rats are administered drug (1-20 mg/kg) or vehicle orally q.d. for fourdays prior to challenge. On day 4, rats are challenged with eithersaline or LPS dissolved in saline (2 mg/kg) via intra-trachealinstallation. Animals are sacrificed via intra-peritoneal sodiumpentobarbitol overdose 3 hours post challenge, and the lungs lavagedwith 14 mL of phosphate buffered saline (PBS). The lung lavage fluid iscentrifuged at 300 g for 3 min, and the supernatant removed. The pelletis resuspended in 1-3 mL of PBS at 4° C. depending on pellet size andnumbers of total leukocytes. A volume of the final cell suspension,containing approximately 240,000 cells, is added to an appropriatevolume of PBS at 4° C. to give a final volume of 220 μL and a finalconcentration of 1×10⁶ cells/mL (final Cytospin suspension). A 100 μLsample (100,000 cells) is loaded onto a cytospin centrifuge and spun for4 min at 55 g. Two slides are prepared per lavage sample, and are fixedand stained in DifQuik. In addition, the resuspended lavage fluid isanalyzed for absolute cell numbers and cell differentials by the CellDyn3700SC hematology analyzer (Abbott Laboratories Inc.).

Compounds of the invention, when tested in this assay, were shown toinhibit LPS induced lung inflammation at doses of less than 20 mg/kg.

Example J Effect of Compounds on LPS-Induced Acute Lung Inflammation inMouse

Mice are administered drug (1-20 mg/kg) or vehicle orally q.d. for fourdays prior to challenge. On day 4, mice are challenged with eithersaline or LPS dissolved in saline (0.15 mg/kg) via intra-trachealinstallation. Animals are sacrificed using an intra-peritoneal sodiumpentobarbitol overdose 6 hours post challenge. After thoracotomy, lungsare lavaged with 3×0.75 mL of PBS. The bronchoalveolar lavage fluid iscentrifuged and the supernatant removed. The pellet is resuspended inPBS at 4° C. Cytospins are prepared and stained for differentiation andenumeration of cell types. In addition, the resuspended lavage fluid isanalyzed for absolute cell numbers and cell differentials by the CellDyn3700SC hematology analyzer (Abbott Laboratories Inc.).

Compounds of the invention may be tested in this assay to show theirability to inhibit LPS induced lung inflammation.

Example K Effect of Compounds on Prostaglandin E2 Synthesis

Prostaglandin E2 (PGE2) is a primary product of arachidonic acid (AA)metabolism. Like most eicosanoids, it does not exist preformed incellular reservoirs. PGE2 synthesis is catalyzed by cyclooxygenase-2(COX-2), an inducible enzyme up-regulated by inflammatory stimuli,cytokines and mitogens. COX-2 up-regulation results in increased PGE2production. Elevated concentrations of PGE2 have been reported inchronic inflammatory conditions such as rheumatoid arthritis and asthma.Inhibition of COX-2 and PGE2 synthesis would be a major target for thefuture treatment of inflammatory arthropathies.

Human umbilical vein endothelial cells (HUVEC-C) are grown to confluencyin gelatin coated plates in the presence of endothelial growth medium(EGM-2). EGM-2 is replaced with RPMI-1640 medium containing 2% fetalbovine serum (FBS) for the assay. HUVEC-Cs are incubated with the testedcompounds for 1 hour before stimulation with IL-1β for 24 hours.Exogenous AA is added for 15 minutes and PGE2 concentration in cellculture supernatants is determined by a competitive enzyme immunoassay(EIA).

The compounds are dissolved at a concentration of 20 mM in DMSO, andtested in the assay at 5 and 1 μM with final DMSO concentration of0.05%. Samples are tested in triplicates. Controls included in eachexperiment are: untreated cells, IL-13 treated cells, NS-398/IL-1βtreated cells and a standard curve of known concentrations of PGE2.NS-398 is a selective inhibitor of COX-2 activity. PGE2 concentration iscalculated by log-logit curve fit software and plotted versus PGE2concentration in a standard curve.

Percent inhibition is calculated as: % I=100−[PGE2]_(C)/[PGE2]_(Co)×100,where [PGE2]_(C) is the concentration of PGE2 in compound/IL-1β treatedsamples and [PGE2]_(Co) is the concentration of PGE2 in IL-1β treatedsample.

Compounds of the invention were shown to inhibit PGE2 synthesis atconcentrations of less than 10 μM.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet, are incorporated herein byreference, in their entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1.-23. (canceled)
 24. A method of treating an inflammatory condition ordisease in a mammal, which method comprises administering to the mammalin need thereof a therapeutically effective amount of a compound offormula (I):

wherein: the A, C or D ring is independently fully saturated, partiallysaturated or fully unsaturated; C1, C4, C11, C12, C15 and C16 are eachindependently substituted with two of the following, which areindependently selected: hydrogen, alkyl, —R⁸—OR⁷, or —R⁸—N(R⁷)₂,provided that C4 is not substituted by two methyl groups; C9 and C14 areeach independently substituted with hydrogen, alkyl, —R⁸—OR⁷, or—R⁸—N(R⁷)₂; R¹ is —OR⁷ or —N(R⁷)₂; R² and R³ are each independentlyselected from the group consisting of —R⁸—OR⁷, —R⁸—OC(O)R⁹, —R¹⁰—N(R⁷)₂,—R¹⁰—N(R⁹)C(O)R⁹, —R¹⁰—N(R⁹)S(O)_(t)R⁹ (where t is 1 or 2),—R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkenyl; R^(4a) and R^(4b) are each independently selectedfrom hydrogen, alkyl, alkenyl or alkynyl; or R^(4a) is hydrogen, alkyl,alkenyl or alkynyl and R^(4b) is a direct bond to the carbon at C16; orR^(4a) and R^(4b) together form alkylidene or haloalkylidene; R⁵ isalkyl or R⁵ is a direct bond to the carbon at C14; R⁶ is hydrogen,—R⁸—OR⁷ or —R⁸—N(R⁷)₂; each R⁷ is independently selected from the groupconsisting of hydrogen, —R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroarylalkyl; each R⁸ is independentlyselected from the group consisting of a direct bond, a straight orbranched alkylene chain, and a straight or branched alkenylene chain;each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl; and each R¹⁰ is independently selected from thegroup consisting of a straight or branched alkylene and a straight orbranched alkenylene chain; as a single stereoisomer, a mixture ofstereoisomers, or as a racemic mixture of stereoisomers; or apharmaceutically acceptable salt, solvate or prodrug thereof, inisolation or in a mixture.
 25. The method of claim 24 wherein thecompound of formula (I) is a compound of formula (Ia):

wherein: the A, C or D ring is independently fully saturated orpartially saturated; C1, C4, C11, C12, C15 and C16 are eachindependently substituted with two hydrogens; C9 and C14 are eachindependently substituted with hydrogen; R¹ is —OR⁷ or —N(R⁷)₂; R² andR³ are each independently selected from the group consisting of —R⁸—OR⁷,—R⁸—OC(O)R⁹, —R¹⁰—N(R⁷)₂, —R¹⁰—N(R⁹)C(O)R⁹, —R¹⁰—N(R⁹)S(O)_(t)R⁹ (wheret is 1 or 2), —R¹⁰—N(R⁹)C(NR⁹)N(R⁹)₂, alkyl, alkenyl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroarylalkyl,optionally substituted heteroarylalkenyl, and optionally substitutedheteroarylalkenyl; R^(4a) and R^(4b) are each independently selectedfrom hydrogen, alkyl, alkenyl or alkynyl; or R^(4a) is hydrogen, alkyl,alkenyl or alkynyl and R^(4b) is a direct bond to the carbon at C16; orR^(4a) and R^(4b) together form alkylidene or haloalkylidene; R⁵ isalkyl or R⁵ is a direct bond to the carbon at C14; R⁶ is hydrogen,—R⁸—OR⁷ or —R⁸—N(R⁷)₂ each R⁷ is independently selected from the groupconsisting of hydrogen, —R¹⁰—OR⁹, —R¹⁰—N(R⁹)₂, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroarylalkyl; each R⁸ is independentlyselected from the group consisting of a direct bond, a straight orbranched alkylene chain, and a straight or branched alkenylene chain;each R⁹ is independently selected from the group consisting of hydrogen,alkyl, aryl and aralkyl; and each R¹⁰ is independently selected from thegroup consisting of a straight or branched alkylene and a straight orbranched alkenylene chain.
 26. The method of claim 24 or claim 25wherein the inflammatory condition or disease is selected from the groupconsisting of the following: arthritis (including rheumatoid arthritis,psoriatic arthritis, ankylosing spondylitis, osteoarthritis, gout, andsynovitis), inflammations of the brain (including multiple sclerosis,Alzheimer's, AIDS dementia, stroke, encephalitis, trauma, andCreutzfeld-Jakob disease), inflammatory bowel disease (including Crohn'sdisease and ulcerative colitis), irritable bowel syndrome,ischemia-reperfusion injury (including myocardial infarction),sarcoidosis, psoriasis, tissue/organ transplant, graft vs host disease,systemic lupus erythematosus, Type I juvenile diabetes, vasculitis,artherosclerosis, cardiomyopathy, autoimmune myocarditis, atopicdermatitis, asthma, allergy, allergic rhinitis, and chronic obstructivepulmonary disease (including emphysema and bronchitis). 27.-28.(canceled)
 29. A method of treating an inflammatory condition or diseasein a mammal, which method comprises administering to the mammal in needthereof a therapeutically effective amount of a compound of formula(II):

wherein: the A, C or D ring is independently fully saturated, partiallysaturated or fully unsaturated; C1, C2, C4, C11, C12, C15 and C16 areeach independently substituted with: (a) one of the following: ═O,═C(R¹⁴)₂, ═C═C(R¹⁴)₂]_(n)— (where n is 2 to 6) and —O—[C(R¹⁴)_(m)]—O—(where m is 1 to 6); or (b) two of the following, which areindependently selected: —R¹⁴, —OR¹⁵ and —N(R¹⁶)₂; C3 is substituted withtwo of the following, independently selected: —R¹⁴, —OR¹⁵ and —N(R¹⁶)₂;C5, C8, C9, C10, C13, C14 and C17 are each independently optionallysubstituted with one of the following: —R¹⁴, —OR¹⁵ and —N(R¹⁶)₂; R¹¹ andR¹² are each independently selected from the group consisting ofhydrogen, halo, ═O, —OR¹⁵, —N(R¹⁶)₂ and a C₁₋₃₀ organic moiety; R¹³ is—R¹⁴, —OR¹⁵, —N(R¹⁶), ═C(R¹⁴)₂, ═C═C(R¹⁴)₂, —[C(R¹⁴)₂]_(n)— (where n is2 to 5) or —O—[C(R¹⁴)₂]_(m)—O— (where m is 1 to 5); each R¹⁴ isindependently selected from hydrogen, halo and C₁₋₃₀ organic moietywhere two geminal R¹⁴ groups may together form a ring with the carbon towhich they are attached; each R¹⁵ is independently selected from thegroup consisting of hydrogen, an oxygen protecting group such that —OR¹⁵is a protected hydroxy group, a leaving group initiator such that —OR¹⁵is a leaving group and a C₁₋₃₀ organic moiety that may optionallycontain at least one heteroatom selected from the group consisting ofboron, halogen, nitrogen, oxygen, phosphorus, silicon and sulfur, wherevicinal —OR¹⁵ groups together with the carbons to which they areattached may form a cyclic structure that protects vicinal hydroxygroups and where geminal —OR¹⁵ groups together with the carbon to whichthey are attached, may form a cyclic structure that protects a carbonylgroup; each R¹⁶ is independently selected from the group consisting ofhydrogen, —OR¹⁷, oxygen (so as to form a nitro or an oxime group), and aC₁₋₃₀ organic moiety that may optionally contain at least one heteroatomselected from the group consisting of boron, halogen, nitrogen, oxygen,phosphorus, silicon and sulfur; or two R¹⁶ groups, together with thenitrogen to which they are attached, form a heterocyclic ring; and eachR¹⁷ is independently selected from hydrogen and a C₁₋₃₀ hydrocarbyl; asa single stereoisomer, a mixture of stereoisomers, or as a racemicmixture of stereoisomers; or a pharmaceutically acceptable salt, solvateor prodrug thereof, in isolation or in a mixture: provided, however,that (1) C4 can not be substituted with two methyl groups (2) R¹³ cannot be ═O or 6-methylhept-2-yl; (3) when C17 is substituted withhydrogen, R¹³ can not be —OH or —OC(O)R where R is methyl, ethyl, phenylor cyclohexyl; (4) when C1, C2, C4, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with hydrogen andhydroxy, C8, C9, C14 and C17 are each substituted with hydrogen, C10 andC13 are each substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)H,R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OCH₃ or—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H; (5) when C1, C2, C4, C11, C12, and C15are each substituted with two hydrogens, C16 is substituted withhydrogen and hydroxy, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, C3 issubstituted with hydrogen and hydroxy, R¹¹ is ═O, and R¹² is —CH₂C(O)OHor —CH₂C(O)OCH₃, R¹³ can not be —C(CH₃)HNHCH₂CH₂N(CH₃)₂,—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H, or —C(CH₃)H—R (where R is5-methylpiperidin-2-yl); (6) when C1, C2, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with hydrogen andhydroxy, C4 is substituted with two hydrogens or C4 is double bonded toC3, C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13are each substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂CN, R¹³ cannot be —C(O)OCH₃; (7) when C1, C2, C4, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with hydrogen andhydroxy, C9, C14 and C17 are each substituted with hydrogen, C10 and C13are each substituted with methyl, R¹¹ is ═O, and R¹² is ═CHC(O)H, R¹³can not be —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H; (8) when C1, C2, C4, C11, C12,C15 and C16 are each substituted with two hydrogens, C3 is substitutedwith hydrogen and hydroxy, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is ═O, andR¹² is —CH₂CH₃, R¹³ can not be —C(CH₃)HOC(O)CH₃; (9) when C1, C2, C4,C11, C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and hydroxy, C5, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is hydroxy, and R¹² is ═CHCH₂OH, R¹³ can not be—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H, or —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H,—C(CH₃)HCH₂CH₂C(CH₂)C(CH₃)₂H, or —C(CH₃)HCHC[CH₂C(CH₃)₂H]H; (10) whenC1, C2, C4, C11, C12, and C15 are each substituted with two hydrogens,C3 is substituted with hydrogen and hydroxy, C5, C8, C9, C14 and C17 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, C16 is substituted with two hydrogens or with one hydrogen andhydroxy, R¹¹ is hydroxy, and R¹² is —CH₂CH₂OH, R¹³ can not be—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H, —C(CH₃)HCH₂OH, —CH₂OH, or —C(CH₃)H—R(where R is 5-methylpiperidin-2-yl); (11) when C1, C2, C4, C11, C12, C15and C16 are each substituted with two hydrogens, C3 is substituted withhydrogen and hydroxy, C5, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is hydroxy,and R¹² is —CH₂CH₃, R¹³ can not be —C(CH₃)HCH₂C(CH₃)HC(CH₃)₂H or—C(OH)HCH₃; (12) when C1, C2, C4, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with hydrogen andhydroxy, C5, C8, C9, C14 and C17 are each substituted with hydrogen, C10and C13 are each substituted with methyl, R¹¹ is hydroxy, and R¹² is—CHCH₂, R¹³ can not be —C(OH)HCH₃; (13) when C1, C4, C11, C12, C15 andC16 are each substituted with two hydrogens, C2 is substituted withhydrogen and hydroxy, C3 is substituted with hydrogen and hydroxy, C5,C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13 areeach substituted with methyl, R¹¹ is —C(O)OH, and R¹³ is—C(CH₃)HC(OH)HC(OH)HC(CH₂CH₃)HC(CH₃)₂H, R¹² can not be —CH₂SH or—CH₂SSCH₂R (where R is hydrogen or a C₁₋₃₀ organic moiety); (14) whenC1, C4, C11, C12, C15 and C16 are each substituted with two hydrogens,C2 is substituted with two hydrogens or with hydrogen and hydroxy, C3 issubstituted with hydrogen and hydroxy, C5, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is —C(O)OH or —CH₂OH, and R¹² is —CH₂OH, R¹³ can not be —CH₂OH,—C(CH₃)HC(OH)HC(OH)HC(CH₃)HC(CH₃)₂H or—C(CH₃)HC(OH)HC(OH)HC(CH₂CH₃)HC(CH₃)₂H; (15) when C1, C2, C11, C12 andC15 are each substituted with two hydrogens, C3 is substituted withhydrogen and hydroxy, C4 is substituted with hydrogen and methyl or withtwo hydrogens, C5 and C9 are each substituted with hydrogen, C8 and C14are each substituted with hydrogen or each are substituted with methyl,C10 and C13 are each substituted with methyl, C16 is substituted withhydrogen and —OC(O)CH₃, R¹¹ is —C(O)H, and R¹² is —C(O)H, R¹³ can not be═C[C(O)OH]CH₂CH₂CHC(CH₃)₂ or —C(CH₃)HCH₂CH₂C(O)OCH₃; (16) when C1, C2,C4, C11, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and hydroxy, C5, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,C12 is substituted with hydrogen and hydroxy, R¹¹ is —CH₂C(O)OH or—CH₂C(O)OCH₃, and R¹² is —NH₂ or —N(CH₃)₃, R¹³ can not be—C(CH₃)HCH₂CH₂C(O)OCH₃ or —C(CH₃)HCH₂CH₂C(O)OH; (17) when C1, C2, C4,C11, C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and hydroxy, C5, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is —NH₂ or —N(CH₃)₂, and R¹² is —CH₂C(O)OH or —CH₂C(O)OCH₃, R¹³ cannot be —C(CH₃)HCH₂CH₂C(O)OCH₃ or —C(CH₃)HCH₂CH₂C(O)OH; (18) when C1, C2,C4, C11, C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and hydroxy, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,R¹¹ is ═NNHC(NH)NH₂, and R¹² is —CH₂CH₂C(O)OH, R¹³ can not be—C(CH₃)NNHC(NH)NH₂); (19a) when C1, C2, C4, C11 and C12 are eachsubstituted with two hydrogens, C3 is substituted with ═O, C8, C14 andC17 are each substituted with hydrogen, C9 is substituted with hydrogenor hydroxy, C10 and C13 are each substituted with methyl, C15 issubstituted with two hydrogens or C15 is substituted with hydrogen anddouble bonded to C16, C16 is substituted with hydrogen or hydroxy and isdouble bonded to C15 or C16 is substituted with ═CH₂OH, R¹¹ is ═O, andR¹² is ═CHC(O)OH, R¹³ can not be —C(CH₃)HC(O)CH₂C(CH₃)HC(CH₃)₂H; (19b)when C1, C2, C4, C11 and C12 are each substituted with two hydrogens, C3is substituted with ═O, C8 and C14 are double bonded to each other, C9is substituted with hydroxy, C10 and C13 are each substituted withmethyl, C15 is substituted with hydrogen and double bonded to C16, C16is substituted with methoxy and double bonded to C15, C17 is substitutedwith hydrogen, R¹¹ is ═O, and R¹² is —CH₂C(O)OCH₃, R¹³ can not be—C(CH₃)HC(O)CH₂C(CH₃)HC(CH₃)₂H; (20) when C1, C2, C4, C11, C12, C15 andC16 are each substituted with two hydrogens, C3 is substituted with ═O,C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13 areeach substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂CN, R¹³ can notbe —C(O)NHR (where R is 5-trifluoromethyl-2-t-butylphenyl) or —C(O)OCH₃;(21) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with ═O, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 is substituted with methyl or —CH₂OC(O)H,C13 is substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂CH₃ or —CH₂I,R¹³ can not be —C(O)CH₃; (22) when C1, C2, C4, C11, C12, C15 and C16 areeach substituted with two hydrogens, C3 is substituted with ═O, C5, C8,C9, C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is —C(O)OH, and R¹² is —C(O)OH, R¹³ can notbe —C(CH₃)HCH₂CH₂C(O)OH or —C(CH₃)HCH₂CH₂CH₃; (23) when C1, C2, C4, C11,C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with ═O, C5, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is —CN, andR¹² is ═O, R¹³ can not be —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H; (24) when C1, C2,C4, C12 and C15 are each substituted with two hydrogens, C3 issubstituted with hydrogen and —OC(O)CH₃, C8, C9, and C14 are eachsubstituted with hydrogen, C11 is substituted with two hydrogens,hydrogen and hydroxy, or hydrogen and —OC(O)CH₃, C16 is substituted withtwo hydrogens or ═CH₂, C17 is substituted with hydrogen, hydroxy or—OC(O)CH₃, C10 and C13 are each substituted with methyl, R¹¹ is ═O, andR¹² is —CH₂C(O)OH, R¹³ can not be —CH₃, —CH₂CH₃, —C(O)CH₃,cyclopentanone, —C(CH₃)HOC(O)R (where R is phenyl),—C(CH₃)HCH₂CH₂C(O)OCH₃, —C(O)CH₂OC(O)CH₃ or—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H; (25) when C1, C2, C4, C11, C12 and C16are each substituted with two hydrogens, C3 is substituted with hydrogenand —OC(O)CH₃, C8 and C9 are each substituted with hydrogen, C10 and C13are each substituted with methyl, C14 is substituted with methyl or—OC(O)CH₃, C15 is substituted with two hydrogens or ═O, C17 issubstituted with hydrogen or —OC(O)CH₃, R¹¹ is ═O, and R¹² is —CH₂C(O)H,R¹³ can not be —C(O)OCH₃, —C(O)CH₃ or —CH₃; (26) when C1, C2, C4, C11,C12, and C15 are each substituted with two hydrogens, C3 is substitutedwith hydrogen and —OC(O)CH₃, C8, C9, and C14 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, C16 issubstituted with two hydrogens or forms a double bond with C17, R¹¹ is═O, and R¹² is —CH₂CN, R¹³ can not be —C(O)CH₃; (27) when C1, C2, C4,C11, C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and —OC(O)CH₃, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 is substituted with hydrogen or—CH₂C(O)OH, C13 is substituted with methyl. R¹¹ is ═O, and R¹² is —CH₂Ior —CH₂C(O)OCH₃, R¹³ can not be —C(O)CH₃; (28) when C1, C2, C4, C11,C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and —OC(O)CH₃, C8, C9, C14 and C17 are eachsubstituted with hydrogen, C10 is substituted with hydrogen or—CH₂C(O)OH, C13 is substituted with methyl, R¹¹ is ═O, and R¹² is —CH₂I,—CHCH₂, —CCH, —C(O)OCH₃ or —CH₂OCH₃, R¹³ can not be —C(CH₃)HOC(O)CH₃;(29) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is ═O, and R¹² is —CH—NCO, —CH₂C(O)N₃ or—C(O)OH, R¹³ can not be —C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H; (30) when C1,C2, C4, C11, C12, C15 and C16 are each substituted with two hydrogens,C3 is substituted with hydrogen and —OC(O)CH₃, C8, C9, and C14 are eachsubstituted with hydrogen, C10 and C13 are each substituted with methyl,C17 is substituted with —OC(O)CH₃, R¹¹ is ═O, and R¹² is —CH₂CHNNHR(where R is 2,4-dinitrophenyl), R¹³ can not be —CH₃; (31) when C1, C4,C11, C12, C15 and C16 are each substituted with two hydrogens, C2 issubstituted with hydrogen and —OC(O)CH₃, C3 is substituted with hydrogenand —OC(O)CH₃, C5, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is —C(O)OH,and R¹² is —C(O)H, R¹³ can not be —C(CH₃)HCH₂CH₂CH₂CH₃; (32) when C1,C4, C11, C12, C15 and C16 are each substituted with two hydrogens, C2 issubstituted with hydrogen and —OC(O)CH₃, C3 is substituted with hydrogenand —OC(O)CH₃, C5, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹⁰ is —C(O)OHor —C(O)OCH₃, and R¹² is —C(O)H, —CH₂SSCH₂R (where R is hydrogen or aC₁₋₃₀ organic moiety), —CH₂OS(O)₂CH₃, or —CH₂OH, R¹³ can not be—C(CH₃)HC[OC(O)CH₃]HC[OC(O)CH₃]HC(CH₂CH₃)HC(CH₃)₂H; (33) when C1, C2,C4, C11, C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and —OC(O)CH₃, C5, C8, C9, C14 and C17 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, R¹¹ is —C(O)OH, and R¹² is —C(O)OH, R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OH; (34) when C1, C2, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with hydrogen and—OC(O)CH₃, C4 is substituted with hydrogen and methyl, C5, C9, C14 andC17 are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is —CH₂C(O)H, and R¹² is ═O, R¹³ can not be—C(CH₃)HCH₂CH₂C(O)C(CH₃)₂H; (35) when C1, C2, C4, C11, C12, C15 and C16are each substituted with two hydrogens, C3 is substituted with hydrogenand —OC(O)CH₃, C5, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, and R¹¹ and R¹²are both —CHNOCH₃ or —CHNOCH₂CH₃, R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OCH₃;(36) when C1, C2, C4, C11, C12 and C15 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OC(O)CH₃, C5, C8, C9,C14 and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, C16 is substituted with hydrogen and —OC(O)CH₃,R¹¹ is —OC(O)CH₃, and R¹² is —CH₂CH₂OC(O)CH₃, R¹³ can not be —C(CH₃)HR(where R is 5-methyl-1-acetylpiperidin-2-yl); (37) when C1, C2, C4, C11,C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and triisopropylsilyloxy, C8, C9, C14 and C17are each substituted with hydrogen, C10 and C13 are each substitutedwith methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)OH, —CH₂C(O)H, —CH₂CH₂N₃,—CH₂CH₂OH, —CH₂CH₂OS(O)₂CH₃ or —CH₂C(O)N₃, R¹³ can not be—C(O)N(CH₂CH₃)₂; (38) when C1, C2, C4, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with hydrogen andtriisopropylsilyloxy, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is ═O, andR¹² is —CH₂C(O)OH, —CH₂C(O)H or —CHC(O)Cl, R¹³ can not be —C(O)OCH₃,(39) when C1, C2, C4, C11, C12, C15 and C16 are each substituted withtwo hydrogens, C3 is substituted with hydrogen and triisopropylsilyloxy,C5, C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13are each substituted with methyl, and R¹¹ and R¹² are both —CHNOCH₃, R¹³can not be —C(CH₃)HCH₂CH₂C(O)OCH₃; (40) when C1, C2, C4, C11, C12, C15and C16 are each substituted with two hydrogens, C3 is substitutedhydrogen and —OC(O)R (where R is 4-nitrophenyl or 3,5-dinitrophenyl),C5, C8, C9, C14 and C17 are each substituted with hydrogen, C10 and C13are each substituted with methyl, R¹¹ is —OH, and R¹² is —CH₂CH₂OC(O)R(where R is 4-nitrophenyl or 3,5-dinitrophenyl), R¹³ can not be—C(CH₃)HCH₂OC(O)R (where R is 4-nitrophenyl or 3,5-dinitrophenyl) or—C(CH₃)HCH₂CH₂C(CH₂CH₃)HC(CH₃)₂H; (41) when C1, C2, C4, C11, C12, C15and C16 are each substituted with two hydrogens, C3 is substituted withhydrogen and —OCH₂OCH₃, C5, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is —CN, andR¹² is —OH or ═O, R¹³ can not be —C(CH₃)HCHCHC(CH₃)HC(CH₃)₂H; (42) whenC1, C2, C4, C11, C12, C15 and C16 are each substituted with twohydrogens, C3 is substituted with hydrogen and —OCH₂CH₂CH₃, C8, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is ═O, and R¹² is —CH₂C(O)OH, R¹³ can notbe —OCH₂CH₂CH₃; (43) when C1, C2, C4, C11, C12, C15 and C16 are eachsubstituted with two hydrogens, C3 is substituted with ═NNHR (where is Ris 2,4-dinitrophenyl), C5, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, and R¹¹ and R¹²are both —C(O)OH, R¹³ can not be —C(CH₃)HCH₂CH₂C(O)OH; (44) when C1, C2,C4, C11, C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and —OCH₂R (where R is phenyl), C5, C9, C14and C17 are each substituted with hydrogen, C10 and C13 are eachsubstituted with methyl, R¹¹ is —CH₂C(O)H, and R¹² is ═O, R¹³ can not be—C(CH₃)HCH₂CH₂C(CH₃)HC(CH₃)₂H; (45) when C1, C2, C4, C11, C12, C15 andC16 are each substituted with two hydrogens, C3 is substituted withhydrogen and —CH₃, C8, C9, C14 and C17 are each substituted withhydrogen, C10 and C13 are each substituted with methyl, R¹¹ is ═O, andR¹² is —C(O)OH, R¹³ can not be —OC(CH₃)₃; and (46) when C1, C2, C4, C11,C12, C15 and C16 are each substituted with two hydrogens, C3 issubstituted with hydrogen and —OC(CH₃)₃, C5, C8, C9, C14 and C17 areeach substituted with hydrogen, C10 and C13 are each substituted withmethyl, R¹¹ is hydroxy, and R¹² is —CH₂OH, R¹³ can not be —OC(CH₃)₃.